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Ma J, Zhang Y, Li J, Dang Y, Hu D. Regulation of histone H3K27 methylation in inflammation and cancer. MOLECULAR BIOMEDICINE 2025; 6:14. [PMID: 40042761 PMCID: PMC11882493 DOI: 10.1186/s43556-025-00254-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 02/17/2025] [Accepted: 02/19/2025] [Indexed: 03/09/2025] Open
Abstract
Inflammation is a multifaceted defense mechanism of the immune system against infection. Chronic inflammation is intricately linked to all stages of tumorigenesis and is therefore associated with an elevated risk of developing serious cancers. Epigenetic mechanisms have the capacity to trigger inflammation as well as facilitate tumor development and transformation within an inflammatory context. They achieve this by dynamically modulating the expression of both pro-inflammatory and anti-inflammatory cytokines, which in turn sustains chronic inflammation. The aberrant epigenetic landscape reconfigures the transcriptional programs of inflammatory and oncogenic genes. This reconfiguration is pivotal in dictating the biological functions of both tumor cells and immune cells. Aberrant histone H3 lysine 27 site (H3K27) methylation has been shown to be involved in biological behaviors such as inflammation development, tumor progression, and immune response. The establishment and maintenance of this repressive epigenetic mark is dependent on the involvement of the responsible histone modifying enzymes enhancer of zeste homologue 2 (EZH2), jumonji domain containing 3 (JMJD3) and ubiquitously transcribed tetratricopeptide repeat gene X (UTX) as well as multiple cofactors. In addition, specific pharmacological agents have been shown to modulate H3K27 methylation levels, thereby modulating inflammation and carcinogenesis. This review comprehensively summarises the current characteristics and clinical significance of epigenetic regulation of H3K27 methylation in the context of inflammatory response and tumor progression.
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Affiliation(s)
- Jing Ma
- Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No. 358 Datong Road, Pudong New Area, Shanghai, 200137, China
| | - Yalin Zhang
- Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No. 358 Datong Road, Pudong New Area, Shanghai, 200137, China
| | - Jingyuan Li
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, (Shanghai University of Traditional Chinese Medicine), Shanghai, 200032, China
| | - Yanqi Dang
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, (Shanghai University of Traditional Chinese Medicine), Shanghai, 200032, China.
| | - Dan Hu
- Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No. 358 Datong Road, Pudong New Area, Shanghai, 200137, China.
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Du H, Zhang Y, Yu X, You X, Wu D, Du Z, Cai Y, Luo Z, Lu H, Liao Z, Ding BS, Zhao Y, Wang Y, Xiao K, Yang F, Gan F, Ning N, Zeng J, Shi P, Zhou Z, Huang S. Inhibition of KDM6B prevents osteoarthritis by blocking growth plate-like H3K27me3 loss in bivalent genes. SCIENCE CHINA. LIFE SCIENCES 2025:10.1007/s11427-024-2676-y. [PMID: 39969745 DOI: 10.1007/s11427-024-2676-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 06/19/2024] [Indexed: 02/20/2025]
Abstract
Osteoarthritis (OA) is the most prevalent joint disorder occurring with articular cartilage degradation. It includes a switch from an articular to a growth plate chondrocyte phenotype. Here, we investigated the histone modification profiles and found significant H3K27me3 loss in OA, which led to disease-associated gene expression. Surprisingly, these genes were occupied by both H3K27me3 and H3K4me3 in normal chondrocytes, showing a poised bivalent state. Furthermore, we observed the derepression of similar bivalent genes in growth plate chondrocytes. Finally, a KDM6B inhibitor GSK-J4 prevented the H3K27me3 loss and cartilage damage in the rat OA model. Our results reveal an inherited bivalent epigenetic signature on developmental genes that makes articular chondrocytes prone to hypertrophy and contributes to a promising epigenetic therapy for OA.
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Affiliation(s)
- Hao Du
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yao Zhang
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xi Yu
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
- Rehabilitation Medicine Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xuanhe You
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Diwei Wu
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ze Du
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yongrui Cai
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhenyu Luo
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hanpeng Lu
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhixin Liao
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Bi-Sen Ding
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
| | - Ya Zhao
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, China
- Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou, 225001, China
| | - Yan Wang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, 611130, China
| | - Ke Xiao
- Department of Lower Limb Surgery of Sichuan Province Orthopedic Hospital, Central Laboratory of Sichuan Province Orthopedic Hospital, Chengdu, 610000, China
| | - Fan Yang
- Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, 518000, China
| | - Fangji Gan
- School of Mechanical Engineering, Sichuan University, Chengdu, 610065, China
| | - Ning Ning
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiancheng Zeng
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Peiliang Shi
- GemPharmatech (Chengdu) Co., Ltd., Chengdu, 610000, China
| | - Zongke Zhou
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Shishu Huang
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Yu W, Li X, Zhang C, Niu P, Wu J, He W, Gao K, Xu Y, Li Y. KDM6B knockdown alleviates sleep deprivation-induced cerebrovascular lesions in APP/PS1 mice by inhibiting PARP16 expression. Biochem Pharmacol 2025; 231:116650. [PMID: 39603516 DOI: 10.1016/j.bcp.2024.116650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 10/22/2024] [Accepted: 11/21/2024] [Indexed: 11/29/2024]
Abstract
Cerebral amyloid angiopathy (CAA) is a neurological disorder in the elderly, involving the deposition of vascular amyloid-β (Aβ). Sleep deprivation (SD) causes memory deficits during CAA. Lysine specific demethylase 6B (KDM6B) is a histone H3 lysine 27-specific demethylase associated with neuronal injury and inflammation. However, the role of KDM6B in CAA has yet to be studied. In the current study, the multi-platform over-water method was used to induce chronic SD in APP/PS1 mice. Pathological analysis revealed that SD exacerbated vascular lesions in this model, as manifested by extensive formation of Aβ-positive deposits. In addition, SD led to a significant increase in the expression of KDM6B in the cerebral cortex of APP/PS1 mice. Next, the effect of KDM6B on CAA progression was explored through loss of function. Further experiments illustrated that KDM6B knockdown diminished SD-induced memory impairment, neuronal injury and vascular lesions in vivo. Additionally, isolated primary cortical neurons were treated with 10 µM Aβ1-42 for 48 h to induce the cell model. As expected, knockdown of KDM6B inhibited the Aβ1-42-induced cytotoxicity in primary neurons. Mechanistically, our results demonstrated that KDM6B knockdown downregulated poly (ADP-ribose) polymerase16 (PARP16) expression by increasing trimethylated lysine 27 on histone 3 (H3K27me3) levels, indicating that KDM6B epigenetically regulated PARP16 expression. Function recovery experiment results further proved that PARP16 overexpression negated the effect of KDM6B knockdown on Aβ1-42-induced cytotoxicity. Overall, our findings uncover an unanticipated role of KDM6B in CAA, and KDM6B may serve as a potential therapeutic target for CAA. Abbreviations: CAA, cerebral amyloid angiopathy; Aβ, amyloid-β; SD, sleep deprivation; KDM6B, lysine specific demethylase 6B; AD, Alzheimer's disease; H3K27me3, trimethylated lysine 27 on histone 3; PARP16, poly (ADP-ribose) polymerase16; AAV2, adeno-associated virus 2; CHIP, chromatin immunoprecipitation; ANOVA, one-way analysis of variance.
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Affiliation(s)
- Wenkai Yu
- Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Henan Engineering Research Center of Neural Function Detection and Regulation, Zhengzhou, Henan, China; National Health Commission Key Laboratory of Prevention and Treatment of Cerebrovascular Disease, Zhengzhou, Henan, China
| | - Xinyu Li
- Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Henan Engineering Research Center of Neural Function Detection and Regulation, Zhengzhou, Henan, China; National Health Commission Key Laboratory of Prevention and Treatment of Cerebrovascular Disease, Zhengzhou, Henan, China
| | - Chan Zhang
- Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Henan Engineering Research Center of Neural Function Detection and Regulation, Zhengzhou, Henan, China
| | - Pengpeng Niu
- Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Henan Engineering Research Center of Neural Function Detection and Regulation, Zhengzhou, Henan, China
| | - Jinghao Wu
- Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Henan Engineering Research Center of Neural Function Detection and Regulation, Zhengzhou, Henan, China
| | - Wenjun He
- Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Henan Engineering Research Center of Neural Function Detection and Regulation, Zhengzhou, Henan, China
| | - Kai Gao
- Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Henan Engineering Research Center of Neural Function Detection and Regulation, Zhengzhou, Henan, China
| | - Yuming Xu
- Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Henan Engineering Research Center of Neural Function Detection and Regulation, Zhengzhou, Henan, China; National Health Commission Key Laboratory of Prevention and Treatment of Cerebrovascular Disease, Zhengzhou, Henan, China; Henan Key Laboratory of Cerebrovascular Diseases, Zhengzhou, Henan, China.
| | - Yusheng Li
- Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Henan Engineering Research Center of Neural Function Detection and Regulation, Zhengzhou, Henan, China; National Health Commission Key Laboratory of Prevention and Treatment of Cerebrovascular Disease, Zhengzhou, Henan, China; Henan Key Laboratory of Cerebrovascular Diseases, Zhengzhou, Henan, China.
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Patel RA, Panche AN, Harke SN. Gut microbiome-gut brain axis-depression: interconnection. World J Biol Psychiatry 2025; 26:1-36. [PMID: 39713871 DOI: 10.1080/15622975.2024.2436854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 11/26/2024] [Accepted: 11/28/2024] [Indexed: 12/24/2024]
Abstract
OBJECTIVES The relationship between the gut microbiome and mental health, particularly depression, has gained significant attention. This review explores the connection between microbial metabolites, dysbiosis, and depression. The gut microbiome, comprising diverse microorganisms, maintains physiological balance and influences health through the gut-brain axis, a communication pathway between the gut and the central nervous system. METHODS Dysbiosis, an imbalance in the gut microbiome, disrupts this axis and worsens depressive symptoms. Factors like diet, antibiotics, and lifestyle can cause this imbalance, leading to changes in microbial composition, metabolism, and immune responses. This imbalance can induce inflammation, disrupt neurotransmitter regulation, and affect hormonal and epigenetic processes, all linked to depression. RESULTS Microbial metabolites, such as short-chain fatty acids and neurotransmitters, are key to gut-brain communication, influencing immune regulation and mood. The altered production of these metabolites is associated with depression. While progress has been made in understanding the gut-brain axis, more research is needed to clarify causative relationships and develop new treatments. The emerging field of psychobiotics and microbiome-targeted therapies shows promise for innovative depression treatments by harnessing the gut microbiome's potential. CONCLUSIONS Epigenetic mechanisms, including DNA methylation and histone modifications, are crucial in how the gut microbiota impacts mental health. Understanding these mechanisms offers new prospects for preventing and treating depression through the gut-brain axis.
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Affiliation(s)
- Ruhina Afroz Patel
- Institute of Biosciences and Technology, MGM University, Aurangabad, India
| | - Archana N Panche
- Institute of Biosciences and Technology, MGM University, Aurangabad, India
| | - Sanjay N Harke
- Institute of Biosciences and Technology, MGM University, Aurangabad, India
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Duan X, Xing Z, Qiao L, Qin S, Zhao X, Gong Y, Li X. The role of histone post-translational modifications in cancer and cancer immunity: functions, mechanisms and therapeutic implications. Front Immunol 2024; 15:1495221. [PMID: 39620228 PMCID: PMC11604627 DOI: 10.3389/fimmu.2024.1495221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 10/18/2024] [Indexed: 12/11/2024] Open
Abstract
Histones play crucial roles in both promoting and repressing gene expression, primarily regulated through post-translational modifications (PTMs) at specific amino acid residues. Histone PTMs, including methylation, acetylation, ubiquitination, phosphorylation, lactylation, butyrylation, and propionylation, act as important epigenetic markers. These modifications influence not only chromatin compaction but also gene expression. Their importance extends to the treatment and prevention of various human diseases, particularly cancer, due to their involvement in key cellular processes. Abnormal histone modifications and the enzymes responsible for these alterations often serve as critical drivers in tumor cell proliferation, invasion, apoptosis, and stemness. This review introduces key histone PTMs and the enzymes responsible for these modifications, examining their impact on tumorigenesis and cancer progression. Furthermore, it explores therapeutic strategies targeting histone PTMs and offers recommendations for identifying new potential therapeutic targets.
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Affiliation(s)
- Xiaohong Duan
- School of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, Tianjin, China
- Institute of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, Tianjin, China
- Medical School, Faculty of Medicine, Tianjin University, Tianjin, China
| | - Zhiyao Xing
- Tianjin University and Health-Biotech United Group Joint Laboratory of Innovative Drug Development and Translational Medicine, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, China
- Department of Respiratory Medicine, Jinnan Hospital, Tianjin University, Tianjin, China
- Department of Respiratory Medicine, Tianjin Jinnan Hospital, Tianjin, China
| | - Lu Qiao
- The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Shan Qin
- Tianjin University and Health-Biotech United Group Joint Laboratory of Innovative Drug Development and Translational Medicine, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, China
| | - Xuejing Zhao
- Tianjin University and Health-Biotech United Group Joint Laboratory of Innovative Drug Development and Translational Medicine, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, China
| | - Yanhua Gong
- School of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, Tianjin, China
- Institute of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, Tianjin, China
- Medical School, Faculty of Medicine, Tianjin University, Tianjin, China
| | - Xueren Li
- Department of Respiratory Medicine, Jinnan Hospital, Tianjin University, Tianjin, China
- Department of Respiratory Medicine, Tianjin Jinnan Hospital, Tianjin, China
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Diab R, Dimachkie L, Zein O, Dakroub A, Eid AH. Intermittent Fasting Regulates Metabolic Homeostasis and Improves Cardiovascular Health. Cell Biochem Biophys 2024; 82:1583-1597. [PMID: 38847940 PMCID: PMC11445340 DOI: 10.1007/s12013-024-01314-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/13/2024] [Indexed: 10/02/2024]
Abstract
Obesity is a leading cause of morbidity and mortality globally. While the prevalence of obesity has been increasing, the incidence of its related complications including dyslipidemia and cardiovascular disease (CVD) has also been rising. Recent research has focused on modalities aimed at reducing obesity. Several modalities have been suggested including behavioral and dietary changes, medications, and bariatric surgery. These modalities differ in their effectiveness and invasiveness, with dietary changes gaining more interest due to their minimal risks compared to other modalities. Specifically, intermittent fasting (IF) has been gaining interest in the past decade. IF is characterized by cycles of alternating fasting and eating windows, with several different forms practiced. IF has been shown to reduce weight and alleviate obesity-related complications. Our review of clinical and experimental studies explores the effects of IF on the lipid profile, white adipose tissue (WAT) dynamics, and the gut microbiome. Notably, IF corrects dyslipidemia, reduces WAT accumulation, and decreases inflammation, which reduces CVD and obesity. This comprehensive analysis details the protective metabolic role of IF, advocating for its integration into public health practices.
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Affiliation(s)
- Rawan Diab
- Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Lina Dimachkie
- Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Omar Zein
- Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Ali Dakroub
- St. Francis Hospital and Heart Center, Roslyn, NY, USA
| | - Ali H Eid
- Department of Basic Medical Sciences, College of Medicine, Qatar University, QU Health, Doha, Qatar.
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Zhu S, Chen W, Masson A, Li YP. Cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis. Cell Discov 2024; 10:71. [PMID: 38956429 PMCID: PMC11219878 DOI: 10.1038/s41421-024-00689-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 05/04/2024] [Indexed: 07/04/2024] Open
Abstract
The initiation of osteogenesis primarily occurs as mesenchymal stem cells undergo differentiation into osteoblasts. This differentiation process plays a crucial role in bone formation and homeostasis and is regulated by two intricate processes: cell signal transduction and transcriptional gene expression. Various essential cell signaling pathways, including Wnt, BMP, TGF-β, Hedgehog, PTH, FGF, Ephrin, Notch, Hippo, and Piezo1/2, play a critical role in facilitating osteoblast differentiation, bone formation, and bone homeostasis. Key transcriptional factors in this differentiation process include Runx2, Cbfβ, Runx1, Osterix, ATF4, SATB2, and TAZ/YAP. Furthermore, a diverse array of epigenetic factors also plays critical roles in osteoblast differentiation, bone formation, and homeostasis at the transcriptional level. This review provides an overview of the latest developments and current comprehension concerning the pathways of cell signaling, regulation of hormones, and transcriptional regulation of genes involved in the commitment and differentiation of osteoblast lineage, as well as in bone formation and maintenance of homeostasis. The paper also reviews epigenetic regulation of osteoblast differentiation via mechanisms, such as histone and DNA modifications. Additionally, we summarize the latest developments in osteoblast biology spurred by recent advancements in various modern technologies and bioinformatics. By synthesizing these insights into a comprehensive understanding of osteoblast differentiation, this review provides further clarification of the mechanisms underlying osteoblast lineage commitment, differentiation, and bone formation, and highlights potential new therapeutic applications for the treatment of bone diseases.
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Affiliation(s)
- Siyu Zhu
- Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, LA, USA
| | - Wei Chen
- Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, LA, USA.
| | - Alasdair Masson
- Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, LA, USA
| | - Yi-Ping Li
- Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, LA, USA.
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Huang Y, Pan W, Ma J. SKP2-mediated ubiquitination and degradation of KLF11 promotes osteoarthritis via modulation of JMJD3/NOTCH1 pathway. FASEB J 2024; 38:e23640. [PMID: 38690715 DOI: 10.1096/fj.202300664rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 03/28/2024] [Accepted: 04/18/2024] [Indexed: 05/02/2024]
Abstract
Osteoarthritis (OA) is the main cause of cartilage damage and disability. This study explored the biological function of S-phase kinase-associated protein 2 (SKP2) and Kruppel-like factor 11 (KLF11) in OA progression and its underlying mechanisms. C28/I2 chondrocytes were stimulated with IL-1β to mimic OA in vitro. We found that SKP2, Jumonji domain-containing protein D3 (JMJD3), and Notch receptor 1 (NOTCH1) were upregulated, while KLF11 was downregulated in IL-1β-stimulated chondrocytes. SKP2/JMJD3 silencing or KLF11 overexpression repressed apoptosis and extracellular matrix (ECM) degradation in chondrocytes. Mechanistically, SKP2 triggered the ubiquitination and degradation of KLF11 to transcriptionally activate JMJD3, which resulted in activation of NOTCH1 through inhibiting H3K27me3. What's more, the in vivo study found that KLF11 overexpression delayed OA development in rats via restraining apoptosis and maintaining the balance of ECM metabolism. Taken together, ubiquitination and degradation of KLF11 regulated by SKP2 contributed to OA progression by activation of JMJD3/NOTCH1 pathway. Our findings provide promising therapeutic targets for OA.
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Affiliation(s)
- Yuanchi Huang
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi Province, P. R. China
| | - Wenjie Pan
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi Province, P. R. China
| | - Jianbing Ma
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi Province, P. R. China
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Kawatake-Kuno A, Li H, Inaba H, Hikosaka M, Ishimori E, Ueki T, Garkun Y, Morishita H, Narumiya S, Oishi N, Ohtsuki G, Murai T, Uchida S. Sustained antidepressant effects of ketamine metabolite involve GABAergic inhibition-mediated molecular dynamics in aPVT glutamatergic neurons. Neuron 2024; 112:1265-1285.e10. [PMID: 38377990 PMCID: PMC11031324 DOI: 10.1016/j.neuron.2024.01.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 12/25/2023] [Accepted: 01/20/2024] [Indexed: 02/22/2024]
Abstract
Despite the rapid and sustained antidepressant effects of ketamine and its metabolites, their underlying cellular and molecular mechanisms are not fully understood. Here, we demonstrate that the sustained antidepressant-like behavioral effects of (2S,6S)-hydroxynorketamine (HNK) in repeatedly stressed animal models involve neurobiological changes in the anterior paraventricular nucleus of the thalamus (aPVT). Mechanistically, (2S,6S)-HNK induces mRNA expression of extrasynaptic GABAA receptors and subsequently enhances GABAA-receptor-mediated tonic currents, leading to the nuclear export of histone demethylase KDM6 and its replacement by histone methyltransferase EZH2. This process increases H3K27me3 levels, which in turn suppresses the transcription of genes associated with G-protein-coupled receptor signaling. Thus, our findings shed light on the comprehensive cellular and molecular mechanisms in aPVT underlying the sustained antidepressant behavioral effects of ketamine metabolites. This study may support the development of potentially effective next-generation pharmacotherapies to promote sustained remission of stress-related psychiatric disorders.
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Affiliation(s)
- Ayako Kawatake-Kuno
- SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029; Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029
| | - Haiyan Li
- SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Hiromichi Inaba
- SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan; Department of Psychiatry, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Momoka Hikosaka
- Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
| | - Erina Ishimori
- SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Takatoshi Ueki
- Department of Integrative Anatomy, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan
| | - Yury Garkun
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029; Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029
| | - Hirofumi Morishita
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029; Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029
| | - Shuh Narumiya
- Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
| | - Naoya Oishi
- SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan; Department of Psychiatry, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Gen Ohtsuki
- Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
| | - Toshiya Murai
- Department of Psychiatry, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Shusaku Uchida
- SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan; Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan; Department of Integrative Anatomy, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan; Kyoto University Medical Science and Business Liaison Organization, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
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10
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Jefferson TB, Wang T, Jefferson WN, Li Y, Hamilton KJ, Wade PA, Williams CJ, Korach KS. Multiple tissue-specific epigenetic alterations regulate persistent gene expression changes following developmental DES exposure in mouse reproductive tissues. Epigenetics 2023; 18:2139986. [PMID: 36328762 PMCID: PMC9980695 DOI: 10.1080/15592294.2022.2139986] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 10/12/2022] [Indexed: 11/06/2022] Open
Abstract
Clinically, developmental exposure to the endocrine disrupting chemical, diethylstilboestrol (DES), results in long-term male and female infertility. Experimentally, developmental exposure to DES results in abnormal reproductive tract phenotypes in male and female mice. Previously, we reported that neonatal DES exposure causes ERα-mediated aberrations in the transcriptome and in DNA methylation in seminal vesicles (SVs) of adult mice. However, only a subset of DES-altered genes could be explained by changes in DNA methylation. We hypothesized that alterations in histone modification may also contribute to the altered transcriptome during SV development. To test this idea, we performed a series of genome-wide analyses of mouse SVs at pubertal and adult developmental stages in control and DES-exposed wild-type and ERα knockout mice. Neonatal DES exposure altered ERα-mediated mRNA and lncRNA expression in adult SV, including genes encoding chromatin-modifying proteins that can impact histone H3K27ac modification. H3K27ac patterns, particularly at enhancers, and DNA methylation were reprogrammed over time during normal SV development and after DES exposure. Some of these reprogramming changes were ERα-dependent, but others were ERα-independent. A substantial number of DES-altered genes had differential H3K27ac peaks at nearby enhancers. Comparison of gene expression changes, H3K27ac marks and DNA methylation marks between adult SV and adult uterine tissue from ovariectomized mice neonatally exposed to DES revealed that most of the epigenetic changes and altered genes were distinct in the two tissues. These findings indicate that the effects of developmental DES exposure cause reprogramming of reproductive tract tissue differentiation through multiple epigenetic mechanisms.
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Affiliation(s)
- Tanner B. Jefferson
- Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, 27709, USA
| | - Tianyuan Wang
- Integrative Bioinformatics, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, 27709, USA
| | - Wendy N. Jefferson
- Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, 27709, USA
| | - Yin Li
- Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, 27709, USA
| | - Katherine J. Hamilton
- Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, 27709, USA
| | - Paul A. Wade
- Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, 27709, USA
| | - Carmen J. Williams
- Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, 27709, USA
| | - Kenneth S. Korach
- Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, 27709, USA
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11
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Phan QM, Salz L, Kindl SS, Lopez JS, Thompson SM, Makkar J, Driskell IM, Driskell RR. Lineage commitment of dermal fibroblast progenitors is controlled by Kdm6b-mediated chromatin demethylation. EMBO J 2023; 42:e113880. [PMID: 37602956 PMCID: PMC10548174 DOI: 10.15252/embj.2023113880] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 07/26/2023] [Accepted: 08/01/2023] [Indexed: 08/22/2023] Open
Abstract
Dermal Fibroblast Progenitors (DFPs) differentiate into distinct fibroblast lineages during skin development. However, the epigenetic mechanisms that regulate DFP differentiation are not known. Our objective was to use multimodal single-cell approaches, epigenetic assays, and allografting techniques to define a DFP state and the mechanism that governs its differentiation potential. Our initial results indicated that the overall transcription profile of DFPs is repressed by H3K27me3 and has inaccessible chromatin at lineage-specific genes. Surprisingly, the repressive chromatin profile of DFPs renders them unable to reform the skin in allograft assays despite their multipotent potential. We hypothesized that chromatin derepression was modulated by the H3K27me3 demethylase, Kdm6b/Jmjd3. Dermal fibroblast-specific deletion of Kdm6b/Jmjd3 in mice resulted in adipocyte compartment ablation and inhibition of mature dermal papilla functions, confirmed by additional single-cell RNA-seq, ChIP-seq, and allografting assays. We conclude that DFPs are functionally derepressed during murine skin development by Kdm6b/Jmjd3. Our studies therefore reveal a multimodal understanding of how DFPs differentiate into distinct fibroblast lineages and provide a novel publicly available multiomics search tool.
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Affiliation(s)
- Quan M Phan
- School of Molecular BiosciencesWashington State UniversityPullmanWAUSA
| | - Lucia Salz
- North Rhine‐Westphalia Technical University of AachenAachenGermany
| | - Sam S Kindl
- School of Molecular BiosciencesWashington State UniversityPullmanWAUSA
| | - Jayden S Lopez
- School of Molecular BiosciencesWashington State UniversityPullmanWAUSA
| | - Sean M Thompson
- School of Molecular BiosciencesWashington State UniversityPullmanWAUSA
| | - Jasson Makkar
- School of Molecular BiosciencesWashington State UniversityPullmanWAUSA
| | - Iwona M Driskell
- School of Molecular BiosciencesWashington State UniversityPullmanWAUSA
| | - Ryan R Driskell
- School of Molecular BiosciencesWashington State UniversityPullmanWAUSA
- Center for Reproductive BiologyWashington State UniversityPullmanWAUSA
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12
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Goswami S, Raychaudhuri D, Singh P, Natarajan SM, Chen Y, Poon C, Hennessey M, Tannir AJ, Zhang J, Anandhan S, Kerrigan BP, Macaluso MD, He Z, Jindal S, Lang FF, Basu S, Sharma P. Myeloid-specific KDM6B inhibition sensitizes glioblastoma to PD1 blockade. NATURE CANCER 2023; 4:1455-1473. [PMID: 37653141 DOI: 10.1038/s43018-023-00620-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 07/21/2023] [Indexed: 09/02/2023]
Abstract
Glioblastoma (GBM) tumors are enriched in immune-suppressive myeloid cells and are refractory to immune checkpoint therapy (ICT). Targeting epigenetic pathways to reprogram the functional phenotype of immune-suppressive myeloid cells to overcome resistance to ICT remains unexplored. Single-cell and spatial transcriptomic analyses of human GBM tumors demonstrated high expression of an epigenetic enzyme-histone 3 lysine 27 demethylase (KDM6B)-in intratumoral immune-suppressive myeloid cell subsets. Importantly, myeloid cell-specific Kdm6b deletion enhanced proinflammatory pathways and improved survival in GBM tumor-bearing mice. Mechanistic studies showed that the absence of Kdm6b enhances antigen presentation, interferon response and phagocytosis in myeloid cells by inhibition of mediators of immune suppression including Mafb, Socs3 and Sirpa. Further, pharmacological inhibition of KDM6B mirrored the functional phenotype of Kdm6b-deleted myeloid cells and enhanced anti-PD1 efficacy. This study thus identified KDM6B as an epigenetic regulator of the functional phenotype of myeloid cell subsets and a potential therapeutic target for enhanced response to ICT.
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Affiliation(s)
- Sangeeta Goswami
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Deblina Raychaudhuri
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Pratishtha Singh
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Seanu Meena Natarajan
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yulong Chen
- Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Candice Poon
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mercedes Hennessey
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Aminah J Tannir
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jan Zhang
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Swetha Anandhan
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Marc D Macaluso
- Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Zhong He
- Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sonali Jindal
- Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Frederick F Lang
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sreyashi Basu
- Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Padmanee Sharma
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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13
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Li A, Zheng W, Xiao B, Huang W, Li L, Luo M, Liu Z, Chu B, Jiang Y. Design, synthesis and biological evaluation of pyrimidine base hydroxamic acid derivatives as dual JMJD3 and HDAC inhibitors. Bioorg Med Chem Lett 2023; 94:129466. [PMID: 37660833 DOI: 10.1016/j.bmcl.2023.129466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 08/29/2023] [Accepted: 08/29/2023] [Indexed: 09/05/2023]
Abstract
The Jumonji domain-containing protein demethylase 3 (JMJD3) and histone deacetylase (HADC) are related to various cancers and regard as antitumor targets for drug discovery. In this study, based on rational drug design strategy, we designed and synthesized a series of pyrimidine derivatives with hydroxamic acid as novel dual JMJD3 and HDAC inhibitors for synergistic cancer treatment. Compound A5b exhibited inhibitory potency against JMJD3 and HDAC1/6 simultaneously and favorable cytotoxicity against human cancer cells such as A549 and U937. Furthermore, mechanistic studies showed that A5b treatment in A549 cells increased the hypermethylation of histone H3K27 and hyperacetylation of H3K9, suppressed clonogenicity, migration and invasion of cancer cells. Besides, A5b induced apoptosis via the cleavage of caspase-7 and PARP, and G1 cell cycle arrest via upregulated p21 expression. All these results suggested that A5b was the first dual inhibitor against JMJD3 and HDAC and can be a potential compound for cancer therapy.
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Affiliation(s)
- Anqi Li
- Department of Chemistry, Tsinghua University, Beijing 100084, China
| | - Wenwen Zheng
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China
| | - Boren Xiao
- Department of Chemistry, Tsinghua University, Beijing 100084, China
| | - Wenjun Huang
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China
| | - Lulu Li
- State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, China
| | - Minglang Luo
- State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, China
| | - Zijian Liu
- Shenzhen Bay Biopharm Co., Ltd, Shenzhen 518057, China; Shenzhen Winkey Technology Co., Ltd, Shenzhen 518055, China.
| | - Bizhu Chu
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China.
| | - Yuyang Jiang
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China; State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, China; School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China; Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen 518132, China
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14
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Rots D, Jakub TE, Keung C, Jackson A, Banka S, Pfundt R, de Vries BBA, van Jaarsveld RH, Hopman SMJ, van Binsbergen E, Valenzuela I, Hempel M, Bierhals T, Kortüm F, Lecoquierre F, Goldenberg A, Hertz JM, Andersen CB, Kibæk M, Prijoles EJ, Stevenson RE, Everman DB, Patterson WG, Meng L, Gijavanekar C, De Dios K, Lakhani S, Levy T, Wagner M, Wieczorek D, Benke PJ, Lopez Garcia MS, Perrier R, Sousa SB, Almeida PM, Simões MJ, Isidor B, Deb W, Schmanski AA, Abdul-Rahman O, Philippe C, Bruel AL, Faivre L, Vitobello A, Thauvin C, Smits JJ, Garavelli L, Caraffi SG, Peluso F, Davis-Keppen L, Platt D, Royer E, Leeuwen L, Sinnema M, Stegmann APA, Stumpel CTRM, Tiller GE, Bosch DGM, Potgieter ST, Joss S, Splitt M, Holden S, Prapa M, Foulds N, Douzgou S, Puura K, Waltes R, Chiocchetti AG, Freitag CM, Satterstrom FK, De Rubeis S, Buxbaum J, Gelb BD, Branko A, Kushima I, Howe J, Scherer SW, Arado A, Baldo C, Patat O, Bénédicte D, Lopergolo D, Santorelli FM, Haack TB, Dufke A, Bertrand M, Falb RJ, Rieß A, Krieg P, Spranger S, Bedeschi MF, Iascone M, Josephi-Taylor S, Roscioli T, Buckley MF, Liebelt J, Dagli AI, Aten E, Hurst ACE, Hicks A, et alRots D, Jakub TE, Keung C, Jackson A, Banka S, Pfundt R, de Vries BBA, van Jaarsveld RH, Hopman SMJ, van Binsbergen E, Valenzuela I, Hempel M, Bierhals T, Kortüm F, Lecoquierre F, Goldenberg A, Hertz JM, Andersen CB, Kibæk M, Prijoles EJ, Stevenson RE, Everman DB, Patterson WG, Meng L, Gijavanekar C, De Dios K, Lakhani S, Levy T, Wagner M, Wieczorek D, Benke PJ, Lopez Garcia MS, Perrier R, Sousa SB, Almeida PM, Simões MJ, Isidor B, Deb W, Schmanski AA, Abdul-Rahman O, Philippe C, Bruel AL, Faivre L, Vitobello A, Thauvin C, Smits JJ, Garavelli L, Caraffi SG, Peluso F, Davis-Keppen L, Platt D, Royer E, Leeuwen L, Sinnema M, Stegmann APA, Stumpel CTRM, Tiller GE, Bosch DGM, Potgieter ST, Joss S, Splitt M, Holden S, Prapa M, Foulds N, Douzgou S, Puura K, Waltes R, Chiocchetti AG, Freitag CM, Satterstrom FK, De Rubeis S, Buxbaum J, Gelb BD, Branko A, Kushima I, Howe J, Scherer SW, Arado A, Baldo C, Patat O, Bénédicte D, Lopergolo D, Santorelli FM, Haack TB, Dufke A, Bertrand M, Falb RJ, Rieß A, Krieg P, Spranger S, Bedeschi MF, Iascone M, Josephi-Taylor S, Roscioli T, Buckley MF, Liebelt J, Dagli AI, Aten E, Hurst ACE, Hicks A, Suri M, Aliu E, Naik S, Sidlow R, Coursimault J, Nicolas G, Küpper H, Petit F, Ibrahim V, Top D, Di Cara F, Louie RJ, Stolerman E, Brunner HG, Vissers LELM, Kramer JM, Kleefstra T. The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder. Am J Hum Genet 2023; 110:963-978. [PMID: 37196654 PMCID: PMC10257005 DOI: 10.1016/j.ajhg.2023.04.008] [Show More Authors] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 04/24/2023] [Indexed: 05/19/2023] Open
Abstract
De novo variants are a leading cause of neurodevelopmental disorders (NDDs), but because every monogenic NDD is different and usually extremely rare, it remains a major challenge to understand the complete phenotype and genotype spectrum of any morbid gene. According to OMIM, heterozygous variants in KDM6B cause "neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities." Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable. Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.). Using 3D protein structure analysis and an innovative dual Drosophila gain-of-function assay, we demonstrated a disruptive effect of 11 missense/in-frame indels located in or near the enzymatic JmJC or Zn-containing domain of KDM6B. Consistent with the role of KDM6B in human cognition, we demonstrated a role for the Drosophila KDM6B ortholog in memory and behavior. Taken together, we accurately define the broad clinical spectrum of the KDM6B-related NDD, introduce an innovative functional testing paradigm for the assessment of KDM6B variants, and demonstrate a conserved role for KDM6B in cognition and behavior. Our study demonstrates the critical importance of international collaboration, sharing of clinical data, and rigorous functional analysis of genetic variants to ensure correct disease diagnosis for rare disorders.
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Affiliation(s)
- Dmitrijs Rots
- Radboudumc, Department of Human Genetics, Nijmegen, the Netherlands
| | - Taryn E Jakub
- Dalhousie University, Department of Biochemistry and Molecular Biology, Faculty of Medicine, Halifax, NS, Canada
| | - Crystal Keung
- Dalhousie University, Department of Biochemistry and Molecular Biology, Faculty of Medicine, Halifax, NS, Canada
| | - Adam Jackson
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Siddharth Banka
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK
| | - Rolph Pfundt
- Radboudumc, Department of Human Genetics, Nijmegen, the Netherlands
| | | | | | - Saskia M J Hopman
- Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Ellen van Binsbergen
- Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Irene Valenzuela
- Hospital Universitari Vall D'Hebron, Clinical and Molecular Genetics Unit, Barcelona, Catalonia, Spain
| | - Maja Hempel
- Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tatjana Bierhals
- Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Fanny Kortüm
- Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Francois Lecoquierre
- University Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Disorders, 76000 Rouen, France
| | - Alice Goldenberg
- University Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Disorders, 76000 Rouen, France
| | - Jens Michael Hertz
- Odense University Hospital, Department of Clinical Genetics, Odense, Denmark; University of Southern Denmark, Department of Clinical Research, Odense, Denmark
| | | | - Maria Kibæk
- Department of Pediatrics, Odense University Hospital, Odense, Denmark
| | | | | | | | | | - Linyan Meng
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics Laboratories, Houston, TX 77021, USA
| | - Charul Gijavanekar
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics Laboratories, Houston, TX 77021, USA
| | - Karl De Dios
- Division of Medical Genetics, Dayton Children's Hospital, Dayton, OH, USA
| | - Shenela Lakhani
- Center for Neurogenetics, Weill Cornell Medicine, Brain and Mind Research Institute, New York, NY, USA
| | - Tess Levy
- Center for Neurogenetics, Weill Cornell Medicine, Brain and Mind Research Institute, New York, NY, USA
| | - Matias Wagner
- Institute of Human Genetics, School of Medicine, Technical University Munich, Munich, Germany; Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany; Division of Pediatric Neurology, Department of Pediatrics, Dr. von Hauner Children's Hospital, LMU University Hospital, Munich, Germany
| | - Dagmar Wieczorek
- Institute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
| | - Paul J Benke
- Division of Genetics, Joe DiMaggio Children's Hospital, Hollywood, FL, USA
| | | | - Renee Perrier
- Department of Medical Genetics, Alberta Children's Hospital and Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Sergio B Sousa
- Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Pedro M Almeida
- Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Maria José Simões
- CBR Genomics, Cantanhede, Portugal; Genoinseq, Next-Generation Sequencing Unit, Biocant, Cantanhede, Portugal
| | - Bertrand Isidor
- Service de Génétique Médicale, CHU Nantes, 44093 Nantes, France; Université de Nantes, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, 44007 Nantes, France
| | - Wallid Deb
- Service de Génétique Médicale, CHU Nantes, 44093 Nantes, France; Université de Nantes, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, 44007 Nantes, France
| | - Andrew A Schmanski
- Department of Genetic Medicine, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA
| | - Omar Abdul-Rahman
- Department of Genetic Medicine, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA
| | - Christophe Philippe
- Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, Dijon, France; Inserm, UMR1231, Equipe GAD, Bâtiment B3, Université de Bourgogne Franche Comté, Dijon Cedex, France
| | - Ange-Line Bruel
- Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, Dijon, France; Inserm, UMR1231, Equipe GAD, Bâtiment B3, Université de Bourgogne Franche Comté, Dijon Cedex, France
| | - Laurence Faivre
- Inserm, UMR1231, Equipe GAD, Bâtiment B3, Université de Bourgogne Franche Comté, Dijon Cedex, France; Centre de Référence Maladies Rares "Anomalies du développement et syndromes malformatifs", Centre de Génétique, FHU-TRANSLAD et Institut GIMI, CHU Dijon Bourgogne, Dijon, France
| | - Antonio Vitobello
- Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, Dijon, France; Inserm, UMR1231, Equipe GAD, Bâtiment B3, Université de Bourgogne Franche Comté, Dijon Cedex, France
| | - Christel Thauvin
- Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, Dijon, France; Inserm, UMR1231, Equipe GAD, Bâtiment B3, Université de Bourgogne Franche Comté, Dijon Cedex, France; Centre de Référence Déficiences Intellectuelles de Causes Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France
| | - Jeroen J Smits
- Radboudumc, Department of Human Genetics, Nijmegen, the Netherlands
| | - Livia Garavelli
- Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Stefano G Caraffi
- Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Francesca Peluso
- Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Laura Davis-Keppen
- University of South Dakota Sanford School of Medicine and Sanford Children's Hospital, Sioux Falls, SD, USA
| | - Dylan Platt
- University of South Dakota Sanford School of Medicine and Sanford Children's Hospital, Sioux Falls, SD, USA
| | - Erin Royer
- University of South Dakota Sanford School of Medicine and Sanford Children's Hospital, Sioux Falls, SD, USA
| | - Lisette Leeuwen
- University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands
| | - Margje Sinnema
- Maastricht University Medical Center, Department of Clinical Genetics, Maastricht, the Netherlands
| | - Alexander P A Stegmann
- Maastricht University Medical Center, Department of Clinical Genetics, Maastricht, the Netherlands
| | - Constance T R M Stumpel
- Maastricht University Medical Center, Department of Clinical Genetics, Maastricht, the Netherlands; Department of Clinical Genetics and GROW-School for Oncology and Reproduction, Maastricht, the Netherlands
| | - George E Tiller
- Kaiser Permanente, Department of Genetics, Los Angeles, CA, USA
| | | | | | - Shelagh Joss
- West of Scotland Regional Genetics Service, Laboratory Medicine Building, Queen Elizabeth University Hospital, Glasgow, UK
| | - Miranda Splitt
- Northern Genetics Service, Institute of Genetic Medicine, International Centre for Life, Newcastle Upon Tyne NE1 3BZ, UK
| | - Simon Holden
- Department of Clinical Genetics, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
| | - Matina Prapa
- Department of Clinical Genetics, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
| | - Nicola Foulds
- Wessex Clinical Genetics Services, University Hospital Southampton NHS Foundation Trust, Southampton SO16 5YA, UK
| | - Sofia Douzgou
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
| | - Kaija Puura
- Department of Child Psychiatry, Tampere University and Tampere University Hospital, Tampere, Finland
| | - Regina Waltes
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, Goethe-Universität, Frankfurt am Main, Germany
| | - Andreas G Chiocchetti
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, Goethe-Universität, Frankfurt am Main, Germany
| | - Christine M Freitag
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, Goethe-Universität, Frankfurt am Main, Germany
| | - F Kyle Satterstrom
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Silvia De Rubeis
- Mindich Child Health and Development Institute and Departments of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Joseph Buxbaum
- Mindich Child Health and Development Institute and Departments of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Bruce D Gelb
- Mindich Child Health and Development Institute and Departments of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Aleksic Branko
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Itaru Kushima
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan; Medical Genomics Center, Nagoya University Hospital, Nagoya, Japan
| | - Jennifer Howe
- The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada
| | - Stephen W Scherer
- The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada
| | - Alessia Arado
- Laboratory of Human Genetics, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Chiara Baldo
- Laboratory of Human Genetics, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Olivier Patat
- Service de Génétique Médicale, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | - Demeer Bénédicte
- Service de Génétique Clinique, Centre de référence maladies rares, CHU d'Amiens-site Sud, Amiens, France
| | - Diego Lopergolo
- Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; UOC Neurologia e Malattie Neurometaboliche, Azienda Ospedaliero Universitaria Senese, Policlinico Le Scotte, Viale Bracci, 2, 53100 Siena, Italy; IRCCS Stella Maris Foundation, Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, Pisa, Italy
| | - Filippo M Santorelli
- IRCCS Stella Maris Foundation, Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, Pisa, Italy
| | - Tobias B Haack
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany
| | - Andreas Dufke
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany
| | - Miriam Bertrand
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany
| | - Ruth J Falb
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany
| | - Angelika Rieß
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany
| | - Peter Krieg
- Department of Pediatrics, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany
| | | | | | - Maria Iascone
- Laboratory of Medical Genetics, Ospedale Papa Giovanni XXIII, Bergamo, Italy
| | - Sarah Josephi-Taylor
- Department of Clinical Genetics, The Children's Hospital at Westmead, Sydney, NSW, Australia; Discipline of Genomic Medicine, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Tony Roscioli
- Neuroscience Research Australia, University of New South Wales, Sydney, NSW, Australia; New South Wales Health Pathology Randwick Genomics Laboratory, Sydney, NSW, Australia; Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, NSW 2031, Australia; Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2031, Australia
| | - Michael F Buckley
- New South Wales Health Pathology Randwick Genomics Laboratory, Sydney, NSW, Australia
| | - Jan Liebelt
- South Australian Clinical Genetics Service, Women's and Children's Hospital, Adelaide, SA, Australia
| | - Aditi I Dagli
- Orlando Health Arnold Palmer Hospital for Children, Division of Genetics, Orlando, FL, USA
| | - Emmelien Aten
- Department of Clinical Genetics, Leiden University Medical Center, 2333 Leiden, the Netherlands
| | - Anna C E Hurst
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Alesha Hicks
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Mohnish Suri
- Nottingham Clinical Genetics Service, City Hospital Campus, Nottingham, UK
| | - Ermal Aliu
- Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Sunil Naik
- Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Richard Sidlow
- Valley Children's Hospital, Valley Children's Place, Madera, CA 93636, USA
| | - Juliette Coursimault
- University Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Disorders, 76000 Rouen, France
| | - Gaël Nicolas
- University Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Disorders, 76000 Rouen, France
| | - Hanna Küpper
- Neuropediatric Department, University Hospital Tübingen, Tübingen, Germany
| | - Florence Petit
- Centre Hospitalier Universitaire de Lille, Clinique de Génétique Guy Fontaine, Lille, France
| | - Veyan Ibrahim
- Dalhousie University, Department of Biochemistry and Molecular Biology, Faculty of Medicine, Halifax, NS, Canada; Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
| | - Deniz Top
- Dalhousie University, Department of Biochemistry and Molecular Biology, Faculty of Medicine, Halifax, NS, Canada; Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
| | - Francesca Di Cara
- Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
| | | | | | - Han G Brunner
- Radboudumc, Department of Human Genetics, Nijmegen, the Netherlands; Maastricht University Medical Center, Department of Clinical Genetics, Maastricht, the Netherlands
| | | | - Jamie M Kramer
- Dalhousie University, Department of Biochemistry and Molecular Biology, Faculty of Medicine, Halifax, NS, Canada.
| | - Tjitske Kleefstra
- Radboudumc, Department of Human Genetics, Nijmegen, the Netherlands; Center for Neuropsychiatry, Vincent van Gogh, Venray, the Netherlands; Department of Clinical Genetics, ErasmusMC, Rotterdam, the Netherlands.
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15
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Tang D, Lu Y, Zuo N, Yan R, Wu C, Wu L, Liu S, He Y. The H3K27 demethylase controls the lateral line embryogenesis of zebrafish. Cell Biol Toxicol 2023; 39:1137-1152. [PMID: 34716527 PMCID: PMC10406677 DOI: 10.1007/s10565-021-09669-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 10/11/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND Kdm6b, a specific histone 3 lysine 27 (H3K27) demethylase, has been reported to be implicated in a variety of developmental processes including cell differentiation and cell fate determination and multiple organogenesis. Here, we regulated the transcript level of kdm6bb to study the potential role in controlling the hearing organ development of zebrafish. METHODS A morpholino antisense oligonucleotide (MO) strategy was used to induce Kdm6b deficiency; immunohistochemical staining and in situ hybridization analysis were conducted to figure out the morphologic alterations and embryonic mechanisms. RESULTS Kdm6bb is expressed in the primordium and neuromasts at the early stage of zebrafish embryogenesis, suggesting a potential function of Kdm6b in the development of mechanosensory organs. Knockdown of kdm6bb severely influences the cell migration and proliferation in posterior lateral line primordium, abates the number of neuromasts along the trunk, and mRNA-mediated rescue test can partially renew the neuromasts. Loss of kdm6bb might be related to aberrant expressions of chemokine genes encompassing cxcl12a and cxcr4b/cxcr7b in the migrating primordium. Moreover, inhibition of kdm6bb reduces the expression of genes in Fgf signaling pathway, while it increases the axin2 and lef1 expression level of Wnt/β-catenin signaling during the migrating stage. CONCLUSIONS Collectively, our results revealed that Kdm6b plays an essential role in guiding the migration of primordium and in regulating the deposition of zebrafish neuromasts by mediating the gene expression of chemokines and Wnt and Fgf signaling pathway. Since histone methylation and demethylation are reversible, targeting Kdm6b may present as a novel therapeutic regimen for hearing disorders.
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Affiliation(s)
- Dongmei Tang
- ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, NHC Key Laboratory of Hearing Medicine, Fudan University, 83 Fenyang Road, Shanghai, 200031, China
| | - Yitong Lu
- Department of Otolaryngology-Head and Neck Surgery, Yijishan Hospital of Wannan Medical College, 2 Zheshanwest Road, Wuhu, 241001, Anhui, China
| | - Na Zuo
- Department of Otolaryngology-Head and Neck Surgery, Yijishan Hospital of Wannan Medical College, 2 Zheshanwest Road, Wuhu, 241001, Anhui, China
| | - Renchun Yan
- Department of Otolaryngology-Head and Neck Surgery, Yijishan Hospital of Wannan Medical College, 2 Zheshanwest Road, Wuhu, 241001, Anhui, China
| | - Cheng Wu
- Department of Otolaryngology-Head and Neck Surgery, Yijishan Hospital of Wannan Medical College, 2 Zheshanwest Road, Wuhu, 241001, Anhui, China
| | - Lijuan Wu
- Department of Otolaryngology-Head and Neck Surgery, Yijishan Hospital of Wannan Medical College, 2 Zheshanwest Road, Wuhu, 241001, Anhui, China
| | - Shaofeng Liu
- Department of Otolaryngology-Head and Neck Surgery, Yijishan Hospital of Wannan Medical College, 2 Zheshanwest Road, Wuhu, 241001, Anhui, China.
| | - Yingzi He
- ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, NHC Key Laboratory of Hearing Medicine, Fudan University, 83 Fenyang Road, Shanghai, 200031, China.
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16
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Chen A, Sun Z, Sun D, Huang M, Fang H, Zhang J, Qian G. Integrative bioinformatics and validation studies reveal KDM6B and its associated molecules as crucial modulators in Idiopathic Pulmonary Fibrosis. Front Immunol 2023; 14:1183871. [PMID: 37275887 PMCID: PMC10235501 DOI: 10.3389/fimmu.2023.1183871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 05/08/2023] [Indexed: 06/07/2023] Open
Abstract
Background Idiopathic Pulmonary Fibrosis (IPF) can be described as a debilitating lung disease that is characterized by the complex interactions between various immune cell types and signaling pathways. Chromatin-modifying enzymes are significantly involved in regulating gene expression during immune cell development, yet their role in IPF is not well understood. Methods In this study, differential gene expression analysis and chromatin-modifying enzyme-related gene data were conducted to identify hub genes, common pathways, immune cell infiltration, and potential drug targets for IPF. Additionally, a murine model was employed for investigating the expression levels of candidate hub genes and determining the infiltration of different immune cells in IPF. Results We identified 33 differentially expressed genes associated with chromatin-modifying enzymes. Enrichment analyses of these genes demonstrated a strong association with histone lysine demethylation, Sin3-type complexes, and protein demethylase activity. Protein-protein interaction network analysis further highlighted six hub genes, specifically KDM6B, KDM5A, SETD7, SUZ12, HDAC2, and CHD4. Notably, KDM6B expression was significantly increased in the lungs of bleomycin-induced pulmonary fibrosis mice, showing a positive correlation with fibronectin and α-SMA, two essential indicators of pulmonary fibrosis. Moreover, we established a diagnostic model for IPF focusing on KDM6B and we also identified 10 potential therapeutic drugs targeting KDM6B for IPF treatment. Conclusion Our findings suggest that molecules related to chromatin-modifying enzymes, primarily KDM6B, play a critical role in the pathogenesis and progression of IPF.
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Affiliation(s)
- Anning Chen
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Zhun Sun
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Donglin Sun
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Meiying Huang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Hongwei Fang
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jinyuan Zhang
- Department of Pain, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Guojun Qian
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
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17
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Burlibasa L, Nicu AT, Chifiriuc MC, Medar C, Petrescu A, Jinga V, Stoica I. H3 histone methylation landscape in male urogenital cancers: from molecular mechanisms to epigenetic biomarkers and therapeutic targets. Front Cell Dev Biol 2023; 11:1181764. [PMID: 37228649 PMCID: PMC10203431 DOI: 10.3389/fcell.2023.1181764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 04/27/2023] [Indexed: 05/27/2023] Open
Abstract
During the last decades, male urogenital cancers (including prostate, renal, bladder and testicular cancers) have become one of the most frequently encountered malignancies affecting all ages. While their great variety has promoted the development of various diagnosis, treatment and monitoring strategies, some aspects such as the common involvement of epigenetic mechanisms are still not elucidated. Epigenetic processes have come into the spotlight in the past years as important players in the initiation and progression of tumors, leading to a plethora of studies highlighting their potential as biomarkers for diagnosis, staging, prognosis, and even as therapeutic targets. Thus, fostering research on the various epigenetic mechanisms and their roles in cancer remains a priority for the scientific community. This review focuses on one of the main epigenetic mechanisms, namely, the methylation of the histone H3 at various sites and its involvement in male urogenital cancers. This histone modification presents a great interest due to its modulatory effect on gene expression, leading either to activation (e.g., H3K4me3, H3K36me3) or repression (e.g., H3K27me3, H3K9me3). In the last few years, growing evidence has demonstrated the aberrant expression of enzymes that methylate/demethylate histone H3 in cancer and inflammatory diseases, that might contribute to the initiation and progression of such disorders. We highlight how these particular epigenetic modifications are emerging as potential diagnostic and prognostic biomarkers or targets for the treatment of urogenital cancers.
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Affiliation(s)
| | | | - Mariana Carmen Chifiriuc
- Faculty of Biology, University of Bucharest, Bucharest, Romania
- Academy of Romanian Scientists, Bucharest, Romania
- Romanian Academy, Bucharest, Romania
| | - Cosmin Medar
- University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania
- Clinical Hospital “Prof. dr Theodor Burghele”, Bucharest, Romania
| | - Amelia Petrescu
- Clinical Hospital “Prof. dr Theodor Burghele”, Bucharest, Romania
| | - Viorel Jinga
- Academy of Romanian Scientists, Bucharest, Romania
- University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania
- Clinical Hospital “Prof. dr Theodor Burghele”, Bucharest, Romania
| | - Ileana Stoica
- Faculty of Biology, University of Bucharest, Bucharest, Romania
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18
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Issa N, Bjeije H, Wilson ER, Krishnan A, Dunuwille WMB, Parsons TM, Zhang CR, Han W, Young AL, Ren Z, Ge K, Wang ES, Weng AP, Cashen A, Spencer DH, Challen GA. KDM6B protects T-ALL cells from NOTCH1-induced oncogenic stress. Leukemia 2023; 37:728-740. [PMID: 36797416 PMCID: PMC10081958 DOI: 10.1038/s41375-023-01853-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 02/08/2023] [Accepted: 02/10/2023] [Indexed: 02/18/2023]
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm resulting from the malignant transformation of T-cell progenitors. While activating NOTCH1 mutations are the dominant genetic drivers of T-ALL, epigenetic dysfunction plays a central role in the pathology of T-ALL and can provide alternative mechanisms to oncogenesis in lieu of or in combination with genetic mutations. The histone demethylase enzyme KDM6A (UTX) is also recurrently mutated in T-ALL patients and functions as a tumor suppressor. However, its gene paralog, KDM6B (JMJD3), is never mutated and can be significantly overexpressed, suggesting it may be necessary for sustaining the disease. Here, we used mouse and human T-ALL models to show that KDM6B is required for T-ALL development and maintenance. Using NOTCH1 gain-of-function retroviral models, mouse cells genetically deficient for Kdm6b were unable to propagate T-ALL. Inactivating KDM6B in human T-ALL patient cells by CRISPR/Cas9 showed KDM6B-targeted cells were significantly outcompeted over time. The dependence of T-ALL cells on KDM6B was proportional to the oncogenic strength of NOTCH1 mutation, with KDM6B required to prevent stress-induced apoptosis from strong NOTCH1 signaling. These studies identify a crucial role for KDM6B in sustaining NOTCH1-driven T-ALL and implicate KDM6B as a novel therapeutic target in these patients.
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Affiliation(s)
- Nancy Issa
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Hassan Bjeije
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Elisabeth R Wilson
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Aishwarya Krishnan
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Wangisa M B Dunuwille
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Tyler M Parsons
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Christine R Zhang
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Wentao Han
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Andrew L Young
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Zhizhong Ren
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Kai Ge
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Eunice S Wang
- Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Andrew P Weng
- Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada
| | - Amanda Cashen
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - David H Spencer
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Grant A Challen
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
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19
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Fukushima HS, Takeda H, Nakamura R. Incomplete erasure of histone marks during epigenetic reprogramming in medaka early development. Genome Res 2023; 33:572-586. [PMID: 37117034 PMCID: PMC10234297 DOI: 10.1101/gr.277577.122] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 03/29/2023] [Indexed: 04/30/2023]
Abstract
Epigenetic modifications undergo drastic erasure and reestablishment after fertilization. This reprogramming is required for proper embryonic development and cell differentiation. In mammals, some histone modifications are not completely reprogrammed and play critical roles in later development. In contrast, in nonmammalian vertebrates, most histone modifications are thought to be more intensively erased and reestablished by the stage of zygotic genome activation (ZGA). However, histone modifications that escape reprogramming in nonmammalian vertebrates and their potential functional roles remain unknown. Here, we quantitatively and comprehensively analyzed histone modification dynamics during epigenetic reprogramming in Japanese killifish, medaka (Oryzias latipes) embryos. Our data revealed that H3K27ac, H3K27me3, and H3K9me3 escape complete reprogramming, whereas H3K4 methylation is completely erased during cleavage stage. Furthermore, we experimentally showed the functional roles of such retained modifications at early stages: (i) H3K27ac premarks promoters during the cleavage stage, and inhibition of histone acetyltransferases disrupts proper patterning of H3K4 and H3K27 methylation at CpG-dense promoters, but does not affect chromatin accessibility after ZGA; (ii) H3K9me3 is globally erased but specifically retained at telomeric regions, which is required for maintenance of genomic stability during the cleavage stage. These results expand the understanding of diversity and conservation of reprogramming in vertebrates, and unveil previously uncharacterized functions of histone modifications retained during epigenetic reprogramming.
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Affiliation(s)
- Hiroto S Fukushima
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan
| | - Hiroyuki Takeda
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan
| | - Ryohei Nakamura
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan
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20
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Phan QM, Salz L, Kindl SS, Lopez JS, Thompson SM, Makkar J, Driskell IM, Driskell RR. Lineage Commitment of Dermal Fibroblast Progenitors is Mediated by Chromatin De-repression. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.07.531478. [PMID: 36945417 PMCID: PMC10028926 DOI: 10.1101/2023.03.07.531478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
Dermal Fibroblast Progenitors (DFPs) differentiate into distinct fibroblast lineages during skin development. However, the mechanisms that regulate lineage commitment of naive dermal progenitors to form niches around the hair follicle, dermis, and hypodermis, are unknown. In our study, we used multimodal single-cell approaches, epigenetic assays, and allografting techniques to define a DFP state and the mechanisms that govern its differentiation potential. Our results indicate that the overall chromatin profile of DFPs is repressed by H3K27me3 and has inaccessible chromatin at lineage specific genes. Surprisingly, the repressed chromatin profile of DFPs renders them unable to reform skin in allograft assays despite their multipotent potential. Distinct fibroblast lineages, such as the dermal papilla and adipocytes contained specific chromatin profiles that were de-repressed during late embryogenesis by the H3K27-me3 demethylase, Kdm6b/Jmjd3. Tissue-specific deletion of Kdm6b/Jmjd3 resulted in ablating the adipocyte compartment and inhibiting mature dermal papilla functions in single-cell-RNA-seq, ChIPseq, and allografting assays. Altogether our studies reveal a mechanistic multimodal understanding of how DFPs differentiate into distinct fibroblast lineages, and we provide a novel multiomic search-tool within skinregeneration.org.
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Affiliation(s)
- Quan M. Phan
- School of Molecular Biosciences, Washington State University, Pullman, WA
| | - Lucia Salz
- North Rhine-Westphalia Technical University of Aachen, Aachen, Germany
| | - Sam S. Kindl
- School of Molecular Biosciences, Washington State University, Pullman, WA
| | - Jayden S. Lopez
- School of Molecular Biosciences, Washington State University, Pullman, WA
| | - Sean M. Thompson
- School of Molecular Biosciences, Washington State University, Pullman, WA
| | - Jasson Makkar
- School of Molecular Biosciences, Washington State University, Pullman, WA
| | - Iwona M. Driskell
- School of Molecular Biosciences, Washington State University, Pullman, WA
| | - Ryan R. Driskell
- School of Molecular Biosciences, Washington State University, Pullman, WA
- Center for Reproductive Biology, Washington State University, Pullman, WA
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21
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Moena D, Vargas E, Montecino M. Epigenetic regulation during 1,25-dihydroxyvitamin D 3-dependent gene transcription. VITAMINS AND HORMONES 2023; 122:51-74. [PMID: 36863801 DOI: 10.1016/bs.vh.2023.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
Multiple evidence accumulated over the years, demonstrates that vitamin D-dependent physiological control in vertebrates occurs primarily through the regulation of target gene transcription. In addition, there has been an increasing appreciation of the role of the chromatin organization of the genome on the ability of the active form of vitamin D, 1,25(OH)2D3, and its specific receptor VDR to regulate gene expression. Chromatin structure in eukaryotic cells is principally modulated through epigenetic mechanisms including, but not limited to, a wide number of post-translational modifications of histone proteins and ATP-dependent chromatin remodelers, which are operative in different tissues during response to physiological cues. Hence, there is necessity to understand in depth the epigenetic control mechanisms that operate during 1,25(OH)2D3-dependent gene regulation. This chapter provides a general overview about epigenetic mechanisms functioning in mammalian cells and discusses how some of these mechanisms represent important components during transcriptional regulation of the model gene system CYP24A1 in response to 1,25(OH)2D3.
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Affiliation(s)
- Daniel Moena
- School of Bachelor in Science, Faculty of Life Sciences, Universidad Andres Bello, Concepcion, Chile
| | - Esther Vargas
- School of Medicine, Universidad Andres Bello, Santiago, Chile
| | - Martin Montecino
- Institute of Biomedical Sciences, Faculty of Medicine, Universidad Andres Bello, Santiago, Chile; Millenium Institute Center for Genome Regulation (CRG), Santiago, Chile.
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22
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He C, Liu W, Sun J, Zhang D, Li B. Jumonji domain-containing protein RIOX2 is overexpressed and associated with worse survival outcomes in prostate cancers. Front Oncol 2023; 13:1087082. [PMID: 36776320 PMCID: PMC9911806 DOI: 10.3389/fonc.2023.1087082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 01/09/2023] [Indexed: 01/28/2023] Open
Abstract
Background Histone demethylase RIOX2 was cloned as a c-Myc downstream gene involved in cell proliferation and has been implicated as an oncogenic factor in multiple tumor types. Its expression profiles and correlation with disease progression in prostate cancers are unknown. Methods Transcriptomic profiles of Jumanji domain-containing protein genes were assessed using multiple public expression datasets generated from RNA-seq and cDNA microarray assays. RIOX2 protein expression was assessed using an immunohistochemistry approach on a tissue section array from benign and malignant prostate tissues. Gene expression profiles were analyzed using the bioinformatics software R package. Western blot assay examined androgen stimulation on RIOX2 protein expression in LNCaP cells. Results Among 35 Jumanji domain-containing protein genes, 12 genes were significantly upregulated in prostate cancers compared to benign compartments. COX regression analysis identified that the ribosomal oxygenase 2 (RIOX2) gene was the only one significantly associated with disease-specific survival outcomes in prostate cancer patients. RIOX2 upregulation was confirmed at the protein levels using immunohistochemical assays on prostate cancer tissue sections. Meanwhile, RIOX2 upregulation was associated with clinicopathological features, including late-stage diseases, adverse Gleason scores, TP53 gene mutation, and disease-free status. In castration-resistant prostate cancers (CRPC), RIOX2 expression was positively correlated with AR signaling index but negatively correlated with the neuroendocrinal progression index. However, androgen treatment had no significant stimulatory effect on RIOX2 expression, indicating a parallel but not a causative effect of androgen signaling on RIOX2 gene expression. Further analysis discovered that RIOX2 expression was tightly correlated with its promoter hypomethylation and MYC gene expression, consistent with the notion that RIOX2 was a c-Myc target gene. Conclusion The Jumanji domain-containing protein RIOX2 was significantly overexpressed in prostate cancer, possibly due to c-Myc upregulation. RIOX2 upregulation was identified as an independent prognostic factor for disease-specific survival.
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Affiliation(s)
- Chenchen He
- Department of Radiation Oncology, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Wang Liu
- Department of Urology, The University of Kansas Medical Center, Kansas City, KS, United States
| | - Jiahao Sun
- Department of Radiation Oncology, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Da Zhang
- Department of Pathology & Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS, United States
| | - Benyi Li
- Department of Urology, The University of Kansas Medical Center, Kansas City, KS, United States,Department of Pathology & Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS, United States,*Correspondence: Benyi Li,
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Jiang D, Li T, Guo C, Tang TS, Liu H. Small molecule modulators of chromatin remodeling: from neurodevelopment to neurodegeneration. Cell Biosci 2023; 13:10. [PMID: 36647159 PMCID: PMC9841685 DOI: 10.1186/s13578-023-00953-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 01/03/2023] [Indexed: 01/18/2023] Open
Abstract
The dynamic changes in chromatin conformation alter the organization and structure of the genome and further regulate gene transcription. Basically, the chromatin structure is controlled by reversible, enzyme-catalyzed covalent modifications to chromatin components and by noncovalent ATP-dependent modifications via chromatin remodeling complexes, including switch/sucrose nonfermentable (SWI/SNF), inositol-requiring 80 (INO80), imitation switch (ISWI) and chromodomain-helicase DNA-binding protein (CHD) complexes. Recent studies have shown that chromatin remodeling is essential in different stages of postnatal and adult neurogenesis. Chromatin deregulation, which leads to defects in epigenetic gene regulation and further pathological gene expression programs, often causes a wide range of pathologies. This review first gives an overview of the regulatory mechanisms of chromatin remodeling. We then focus mainly on discussing the physiological functions of chromatin remodeling, particularly histone and DNA modifications and the four classes of ATP-dependent chromatin-remodeling enzymes, in the central and peripheral nervous systems under healthy and pathological conditions, that is, in neurodegenerative disorders. Finally, we provide an update on the development of potent and selective small molecule modulators targeting various chromatin-modifying proteins commonly associated with neurodegenerative diseases and their potential clinical applications.
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Affiliation(s)
- Dongfang Jiang
- grid.458458.00000 0004 1792 6416State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101 China ,grid.410726.60000 0004 1797 8419Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, 100101 China
| | - Tingting Li
- grid.458458.00000 0004 1792 6416State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101 China ,grid.410726.60000 0004 1797 8419Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, 100101 China
| | - Caixia Guo
- grid.9227.e0000000119573309Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation, Beijing, 100101 China ,grid.410726.60000 0004 1797 8419Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, 100101 China
| | - Tie-Shan Tang
- grid.458458.00000 0004 1792 6416State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101 China ,grid.512959.3Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101 China ,grid.410726.60000 0004 1797 8419Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, 100101 China
| | - Hongmei Liu
- grid.458458.00000 0004 1792 6416State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101 China ,grid.512959.3Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101 China
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24
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Xu C, Zhao S, Cai L. Epigenetic (De)regulation in Prostate Cancer. Cancer Treat Res 2023; 190:321-360. [PMID: 38113006 PMCID: PMC11421856 DOI: 10.1007/978-3-031-45654-1_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2023]
Abstract
Prostate cancer (PCa) is a heterogeneous disease exhibiting both genetic and epigenetic deregulations. Epigenetic alterations are defined as changes not based on DNA sequence, which include those of DNA methylation, histone modification, and chromatin remodeling. Androgen receptor (AR) is the main driver for PCa and androgen deprivation therapy (ADT) remains a backbone treatment for patients with PCa; however, ADT resistance almost inevitably occurs and advanced diseases develop termed castration-resistant PCa (CRPC), due to both genetic and epigenetic changes. Due to the reversible nature of epigenetic modifications, inhibitors targeting epigenetic factors have become promising anti-cancer agents. In this chapter, we focus on recent studies about the dysregulation of epigenetic regulators crucially involved in the initiation, development, and progression of PCa and discuss the potential use of inhibitors targeting epigenetic modifiers for treatment of advanced PCa.
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Affiliation(s)
- Chenxi Xu
- Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, 27710, USA
| | - Shuai Zhao
- Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, 27710, USA
| | - Ling Cai
- Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA.
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, 27710, USA.
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25
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Mora VP, Loaiza RA, Soto JA, Bohmwald K, Kalergis AM. Involvement of trained immunity during autoimmune responses. J Autoimmun 2022:102956. [DOI: 10.1016/j.jaut.2022.102956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 11/14/2022] [Indexed: 12/23/2022]
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26
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Zhang Q, Liu Y, Liao J, Wu R, Zhan Y, Zhang P, Luo S. Deficiency of p53 Causes the Inadequate Expression of miR-1246 in B Cells of Systemic Lupus Erythematosus. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 209:1492-1498. [PMID: 36165173 PMCID: PMC9527209 DOI: 10.4049/jimmunol.2200307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 08/15/2022] [Indexed: 01/04/2023]
Abstract
Underexpression of p53 is considered the leading cause of the decreased miR-1246 expression in B cells of systemic lupus erythematosus (SLE) patients, yet the exact mechanism of action still remains unclear. To further explore the molecular mechanism of p53 upregulating miR-1246 expression, we targeted the methylation and acetylation of histone H3 in the miR-1246 promoter region of SLE B cells. We found that increased histone H3 trimethylation at Lys27 (H3K27me3) and decreased histone H3 acetylation at Lys9 and Lys14 (H3K9/K14ac) in the miR-1246 promoter region are essential for the low expression of miR-1246 in SLE B cells. p53 can promote miR-1246 transcription by recruiting Jumonji domain-containing protein 3 (JMJD3), E1A-binding protein p300 (EP300), and CREB-binding protein (CBP) to bind to the miR-1246 promoter, downregulating H3K27me3 and upregulating H3K9/K14ac. Furthermore, early B cell factor 1 (EBF1), CD40, CD38, and X box binding protein-1 (XBP-1) expression levels in SLE B cells transfected with p53 expression plasmid were significantly decreased, whereas autoantibody IgG production in autologous CD4+ T cells cocultured with overexpressed p53 SLE B cells was reduced. Collectively, our data suggest that the reduction of p53 decreases miR-1246 expression via upregulation of H3K27me3 and downregulation of H3K9/14ac, which in turn results in SLE B cell hyperactivity.
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Affiliation(s)
- Qing Zhang
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yu Liu
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jieyue Liao
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ruifang Wu
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yi Zhan
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Peng Zhang
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shuangyan Luo
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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27
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van Zundert B, Montecino M. Epigenetic Changes and Chromatin Reorganization in Brain Function: Lessons from Fear Memory Ensemble and Alzheimer’s Disease. Int J Mol Sci 2022; 23:ijms232012081. [PMID: 36292933 PMCID: PMC9602769 DOI: 10.3390/ijms232012081] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 10/03/2022] [Accepted: 10/05/2022] [Indexed: 11/16/2022] Open
Abstract
Healthy brain functioning in mammals requires a continuous fine-tuning of gene expression. Accumulating evidence over the last three decades demonstrates that epigenetic mechanisms and dynamic changes in chromatin organization are critical components during the control of gene transcription in neural cells. Recent genome-wide analyses show that the regulation of brain genes requires the contribution of both promoter and long-distance enhancer elements, which must functionally interact with upregulated gene expression in response to physiological cues. Hence, a deep comprehension of the mechanisms mediating these enhancer–promoter interactions (EPIs) is critical if we are to understand the processes associated with learning, memory and recall. Moreover, the onset and progression of several neurodegenerative diseases and neurological alterations are found to be strongly associated with changes in the components that support and/or modulate the dynamics of these EPIs. Here, we overview relevant discoveries in the field supporting the role of the chromatin organization and of specific epigenetic mechanisms during the control of gene transcription in neural cells from healthy mice subjected to the fear conditioning paradigm, a relevant model to study memory ensemble. Additionally, special consideration is dedicated to revising recent results generated by investigators working with animal models and human postmortem brain tissue to address how changes in the epigenome and chromatin architecture contribute to transcriptional dysregulation in Alzheimer’s disease, a widely studied neurodegenerative disease. We also discuss recent developments of potential new therapeutic strategies involving epigenetic editing and small chromatin-modifying molecules (or epidrugs).
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Affiliation(s)
- Brigitte van Zundert
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile
- CARE Biomedical Research Center, Santiago 8330005, Chile
- Correspondence: (B.v.Z.); (M.M.)
| | - Martin Montecino
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile
- Millennium Institute Center for Genome Regulation CRG, Santiago 8370186, Chile
- Correspondence: (B.v.Z.); (M.M.)
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28
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Zhou M, Yao Z, Zhao M, Fang Q, Ji X, Chen H, Zhao Y. Molecular Cloning and Expression Responses of Jarid2b to High-Temperature Treatment in Nile Tilapia ( Oreochromis niloticus). Genes (Basel) 2022; 13:1719. [PMID: 36292604 PMCID: PMC9602145 DOI: 10.3390/genes13101719] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 09/12/2022] [Accepted: 09/20/2022] [Indexed: 10/27/2023] Open
Abstract
Nile tilapia is a GSD + TE (Genetic Sex Determination + Temperature Effect) fish, and high-temperature treatment during critical thermosensitive periods (TSP) can induce the sex reversal of Nile tilapia genetic females, and brain transcriptomes have revealed the upregulation of Jarid2 (Jumonji and AT-rich domain containing 2) expression after 36 °C high-temperature treatment for 12 days during TSP. It was shown that JARID2 forms a complex with polycomb repressive complex 2 (PRC2) that catalyzed H3K27me3, which was strongly associated with transcriptional repression. In this study, Jarid2b was cloned and characterized in Nile tilapia, which was highly conserved among the analyzed fish species. The expression of Jarid2b was upregulated in the gonad of 21 dpf XX genetic females after 12-day high-temperature treatment and reached a similar level to that of males. Similar responses to high-temperature treatment also appeared in the brain, heart, liver, muscle, eye, and skin tissues. Interestingly, Jarid2b expression was only in response to high-temperature treatment, and not to 17α-methyltestosterone (MT) or letrozole treatments; although, these treatments can also induce the sex reversal of genetic Nile tilapia females. Further studies revealed that Jarid2b responded rapidly at the 8th hour after high-temperature treatment. Considering that JARID2 can recruit PRC2 and establish H3K27me3, we speculated that it might be an upstream gene participating in the regulation of Nile tilapia GSD + TE through regulating the H3K27 methylation level at the locus of many sex differentiation-related genes.
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Affiliation(s)
| | | | | | | | | | | | - Yan Zhao
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian 271000, China
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29
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Claiborne MD, Leone R. Differential glutamine metabolism in the tumor microenvironment – studies in diversity and heterogeneity: A mini-review. Front Oncol 2022; 12:1011191. [PMID: 36203456 PMCID: PMC9531032 DOI: 10.3389/fonc.2022.1011191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/01/2022] [Indexed: 11/29/2022] Open
Abstract
Increased glutamine metabolism is a hallmark of many cancer types. In recent years, our understanding of the distinct and diverse metabolic pathways through which glutamine can be utilized has grown more refined. Additionally, the different metabolic requirements of the diverse array of cell types within the tumor microenvironment complicate the strategy of targeting any particular glutamine pathway as cancer therapy. In this Mini-Review, we discuss recent advances in further clarifying the cellular fate of glutamine through different metabolic pathways. We further discuss potential promising strategies which exploit the different requirements of cells in the tumor microenvironment as it pertains to glutamine metabolism in an attempt to suppress cancer growth and enhance anti-tumor immune responses.
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Affiliation(s)
- Michael D. Claiborne
- Department of Medicine, Scripps Green Hospital and Scripps Clinic, La Jolla, CA, United States
| | - Robert Leone
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medicine, Baltimore, MD, United States
- *Correspondence: Robert Leone,
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30
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Farooq U, Notani D. Transcriptional regulation of INK4/ARF locus by cis and trans mechanisms. Front Cell Dev Biol 2022; 10:948351. [PMID: 36158211 PMCID: PMC9500187 DOI: 10.3389/fcell.2022.948351] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 08/09/2022] [Indexed: 12/12/2022] Open
Abstract
9p21 locus is one of the most reproducible regions in genome-wide association studies (GWAS). The region harbors CDKN2A/B genes that code for p16INK4a, p15INK4b, and p14ARF proteins, and it also harbors a long gene desert adjacent to these genes. The polymorphisms that are associated with several diseases and cancers are present in these genes and the gene desert region. These proteins are critical cell cycle regulators whose transcriptional dysregulation is strongly linked with cellular regeneration, stemness, aging, and cancers. Given the importance of this locus, intense scientific efforts on understanding the regulation of these genes via promoter-driven mechanisms and recently, via the distal regulatory mechanism have provided major insights. In this review, we describe these mechanisms and propose the ways by which this locus can be targeted in pathologies and aging.
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Affiliation(s)
- Umer Farooq
- Genetics and Development, National Centre for Biological Sciences, Tata Institute for Fundamental Research, Bangalore, India
- The University of Trans-Disciplinary Health Sciences and Technology, Bangalore, India
| | - Dimple Notani
- Genetics and Development, National Centre for Biological Sciences, Tata Institute for Fundamental Research, Bangalore, India
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31
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Li C, Ren J, Zhang M, Wang H, Yi F, Wu J, Tang Y. The heterogeneity of microglial activation and its epigenetic and non-coding RNA regulations in the immunopathogenesis of neurodegenerative diseases. Cell Mol Life Sci 2022; 79:511. [PMID: 36066650 PMCID: PMC11803019 DOI: 10.1007/s00018-022-04536-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 08/21/2022] [Accepted: 08/22/2022] [Indexed: 12/15/2022]
Abstract
Microglia are resident immune cells in the brain and play a central role in the development and surveillance of the nervous system. Extensive gliosis is a common pathological feature of several neurodegenerative diseases, such as Alzheimer's disease (AD), the most common cause of dementia. Microglia can respond to multiple inflammatory insults and later transform into different phenotypes, such as pro- and anti-inflammatory phenotypes, thereby exerting different functions. In recent years, an increasing number of studies based on both traditional bulk sequencing and novel single-cell/nuclear sequencing and multi-omics analysis, have shown that microglial phenotypes are highly heterogeneous and dynamic, depending on the severity and stage of the disease as well as the particular inflammatory milieu. Thus, redirecting microglial activation to beneficial and neuroprotective phenotypes promises to halt the progression of neurodegenerative diseases. To this end, an increasing number of studies have focused on unraveling heterogeneous microglial phenotypes and their underlying molecular mechanisms, including those due to epigenetic and non-coding RNA modulations. In this review, we summarize the epigenetic mechanisms in the form of DNA and histone modifications, as well as the general non-coding RNA regulations that modulate microglial activation during immunopathogenesis of neurodegenerative diseases and discuss promising research approaches in the microglial era.
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Affiliation(s)
- Chaoyi Li
- Aging Research Center, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Jie Ren
- Aging Research Center, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Mengfei Zhang
- Aging Research Center, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Huakun Wang
- Aging Research Center, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Fang Yi
- Aging Research Center, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Junjiao Wu
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Provincial Clinical Research Center for Rheumatic and Immunologic Diseases, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yu Tang
- Aging Research Center, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, 410008, Hunan, China.
- The Biobank of Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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32
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JMJD family proteins in cancer and inflammation. Signal Transduct Target Ther 2022; 7:304. [PMID: 36050314 PMCID: PMC9434538 DOI: 10.1038/s41392-022-01145-1] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 06/22/2022] [Accepted: 08/01/2022] [Indexed: 11/30/2022] Open
Abstract
The occurrence of cancer entails a series of genetic mutations that favor uncontrollable tumor growth. It is believed that various factors collectively contribute to cancer, and there is no one single explanation for tumorigenesis. Epigenetic changes such as the dysregulation of enzymes modifying DNA or histones are actively involved in oncogenesis and inflammatory response. The methylation of lysine residues on histone proteins represents a class of post-translational modifications. The human Jumonji C domain-containing (JMJD) protein family consists of more than 30 members. The JMJD proteins have long been identified with histone lysine demethylases (KDM) and histone arginine demethylases activities and thus could function as epigenetic modulators in physiological processes and diseases. Importantly, growing evidence has demonstrated the aberrant expression of JMJD proteins in cancer and inflammatory diseases, which might serve as an underlying mechanism for the initiation and progression of such diseases. Here, we discuss the role of key JMJD proteins in cancer and inflammation, including the intensively studied histone lysine demethylases, as well as the understudied group of JMJD members. In particular, we focused on epigenetic changes induced by each JMJD member and summarized recent research progress evaluating their therapeutic potential for the treatment of cancer and inflammatory diseases.
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33
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Moon Y, Chae S, Yim S, Yang EG, Choe J, Hyun J, Chang R, Hwang D, Park H. Clioquinol as an inhibitor of JmjC-histone demethylase exhibits common and unique histone methylome and transcriptome between clioquinol and hypoxia. iScience 2022; 25:104517. [PMID: 35754713 PMCID: PMC9218365 DOI: 10.1016/j.isci.2022.104517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 04/08/2022] [Accepted: 05/17/2022] [Indexed: 11/27/2022] Open
Abstract
Clioquinol (CQ) is a hypoxic mimicker to activate hypoxia-inducible factor-1α (HIF-1α) by inhibiting HIF-1α specific asparaginyl hypoxylase (FIH-1). The structural similarity of the Jumonji C (JmjC) domain between FIH-1 and JmjC domain-containing histone lysine demethylases (JmjC-KDMs) led us to investigate whether CQ could inhibit the catalytic activities of JmjC-KDMs. Herein, we showed that CQ inhibits KDM4A/C, KDM5A/B, and KDM6B and affects H3K4me3, H3K9me3, and H3K27me3 marks, respectively. An integrative analysis of the histone methylome and transcriptome data revealed that CQ-mediated JmjC-KDM inhibition altered the transcription of target genes through differential combinations of KDMs and transcription factors. Notably, functional enrichment of target genes showed that CQ and hypoxia commonly affected the response to hypoxia, VEGF signaling, and glycolysis, whereas CQ uniquely altered apoptosis/autophagy and cytoskeleton/extracellular matrix organization. Our results suggest that CQ can be used as a JmjC-KDM inhibitor, HIF-α activator, and an alternative therapeutic agent in hypoxia-based diseases.
Both hypoxia and clioquinol (CQ) inhibit histone lysine demethylases (KDMs) CQ affects H3K4me3, H3K9me3, and H3K27me3 marks upon inhibition CQ treatment-induced histone methylome changes affect target gene transcription Histone methylome predicts TFs underlying transcription of CQ target genes
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Affiliation(s)
- Yunwon Moon
- Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea
| | - Sehyun Chae
- Neurovascular Unit Research Group, Korea Brain Research Institute (KBRI), Daegu 41062, Republic of Korea
| | - Sujin Yim
- Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea
| | - Eun Gyeong Yang
- Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
| | - Jungwoo Choe
- Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea.,Department of Applied Chemistry, University of Seoul, Seoul 02504, Republic of Korea
| | - Jiyeon Hyun
- Department of Applied Chemistry, University of Seoul, Seoul 02504, Republic of Korea
| | - Rakwoo Chang
- Department of Applied Chemistry, University of Seoul, Seoul 02504, Republic of Korea
| | - Daehee Hwang
- School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Hyunsung Park
- Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea.,Department of Applied Chemistry, University of Seoul, Seoul 02504, Republic of Korea
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Jin Y, Liu Z, Li Z, Li H, Zhu C, Li R, Zhou T, Fang B. Histone demethylase JMJD3 downregulation protects against aberrant force-induced osteoarthritis through epigenetic control of NR4A1. Int J Oral Sci 2022; 14:34. [PMID: 35831280 PMCID: PMC9279410 DOI: 10.1038/s41368-022-00190-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 05/27/2022] [Accepted: 06/21/2022] [Indexed: 11/09/2022] Open
Abstract
Osteoarthritis (OA) is a prevalent joint disease with no effective treatment strategies. Aberrant mechanical stimuli was demonstrated to be an essential factor for OA pathogenesis. Although multiple studies have detected potential regulatory mechanisms underlying OA and have concentrated on developing novel treatment strategies, the epigenetic control of OA remains unclear. Histone demethylase JMJD3 has been reported to mediate multiple physiological and pathological processes, including cell differentiation, proliferation, autophagy, and apoptosis. However, the regulation of JMJD3 in aberrant force-related OA and its mediatory effect on disease progression are still unknown. In this work, we confirmed the upregulation of JMJD3 in aberrant force-induced cartilage injury in vitro and in vivo. Functionally, inhibition of JMJD3 by its inhibitor, GSK-J4, or downregulation of JMJD3 by adenovirus infection of sh-JMJD3 could alleviate the aberrant force-induced chondrocyte injury. Mechanistic investigation illustrated that aberrant force induces JMJD3 expression and then demethylates H3K27me3 at the NR4A1 promoter to promote its expression. Further experiments indicated that NR4A1 can regulate chondrocyte apoptosis, cartilage degeneration, extracellular matrix degradation, and inflammatory responses. In vivo, anterior cruciate ligament transection (ACLT) was performed to construct an OA model, and the therapeutic effect of GSK-J4 was validated. More importantly, we adopted a peptide-siRNA nanoplatform to deliver si-JMJD3 into articular cartilage, and the severity of joint degeneration was remarkably mitigated. Taken together, our findings demonstrated that JMJD3 is flow-responsive and epigenetically regulates OA progression. Our work provides evidences for JMJD3 inhibition as an innovative epigenetic therapy approach for joint diseases by utilizing p5RHH-siRNA nanocomplexes.
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Affiliation(s)
- Yu Jin
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Zhen Liu
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Zhenxia Li
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Hairui Li
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Cheng Zhu
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Ruomei Li
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Ting Zhou
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China.
| | - Bing Fang
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China.
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35
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Chen YH, Chen CH, Chien CY, Su YY, Luo SD, Li SH. JMJD3 suppresses tumor progression in oral tongue squamous cell carcinoma patients receiving surgical resection. PeerJ 2022; 10:e13759. [PMID: 35855897 PMCID: PMC9288160 DOI: 10.7717/peerj.13759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 06/29/2022] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Jumonji domain-containing-3 (JMJD3) is reported to be a histone H3 lysine 27 (H3K27) demethylase and a tumor suppressor gene. The present study designed to investigate the crucial role of JMJD3 in oral tongue squamous cell carcinoma (OTSCC) patients who received surgical resection. METHODS We enrolled a total of 156 OTSCC patients receiving surgical resection, including 73 patients (47%) with high expression of JMJD3 and 83 patients (53%) harboring low expression of JMJD3. Two OTSCC cell lines, SAS and Cal 27, were used to explore the modulation of cancer. GSK-J4, a potent inhibitor of JMJD3, was used to treat the two OTSCC cell lines. The Chi-square test was performed to examine between-group differences in categorical variables; the Kaplan-Meier method was used to investigate survival outcome in univariate analysis, and the Cox regression model was used for multivariate analysis. RESULTS The median follow-up period was 59.2 months and he five-year disease-free survival (DFS) and overall survival (OS) rates were 46.2% and 50.0%, respectively. Better five-year DFS (59% versus 35%) and five-year OS (63% versus 39%) were mentioned in patients with high expression of JMJD3 compared to those with low expression of JMJD3. High expression of JMJD3 was significantly associated with superior DFS and OS in the univariate and multivariate analyses. Following successful inhibition of JMJD3 by GSK-J4, western blotting analysis showed the decreased expression of Rb and p21. CONCLUSION Our study showed that high expression of JMJD3 is a good prognostic factor in OTSCC patients who underwent surgical resection.
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Affiliation(s)
- Yen-Hao Chen
- Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Nursing, School of Nursing, Fooyin University, Kaohsiung, Taiwan
| | - Chang-Han Chen
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chih-Yen Chien
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Yan-Ye Su
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Sheng-Dean Luo
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Shau-Hsuan Li
- Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
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Abstract
Histone lysine methylation plays a key role in gene activation and repression. The trimethylation of histone H3 on lysine-27 (H3K27me3) is a critical epigenetic event that is controlled by Jumonji domain-containing protein-3 (JMJD3). JMJD3 is a histone demethylase that specifically removes methyl groups. Previous studies have suggested that JMJD3 has a dual role in cancer cells. JMJD3 stimulates the expression of proliferative-related genes and increases tumor cell growth, propagation, and migration in various cancers, including neural, prostate, ovary, skin, esophagus, leukemia, hepatic, head and neck, renal, lymphoma, and lung. In contrast, JMJD3 can suppress the propagation of tumor cells, and enhance their apoptosis in colorectal, breast, and pancreatic cancers. In this review, we summarized the recent advances of JMJD3 function in cancer cells.
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Zheng B, Liu J, Gao A, Chen X, Gao L, Liao L, Luo B, Ogutu CO, Han Y. Epigenetic reprogramming of H3K27me3 and DNA methylation during leaf-to-callus transition in peach. HORTICULTURE RESEARCH 2022; 9:uhac132. [PMID: 35937864 PMCID: PMC9350832 DOI: 10.1093/hr/uhac132] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 05/29/2022] [Indexed: 05/30/2023]
Abstract
Plant tissues are capable of developing unorganized cell masses termed calluses in response to the appropriate combination of auxin and cytokinin. Revealing the potential epigenetic mechanisms involved in callus development can improve our understanding of the regeneration process of plant cells, which will be beneficial for overcoming regeneration recalcitrance in peach. In this study, we report on single-base resolution mapping of DNA methylation and reprogramming of the pattern of trimethylation of histone H3 at lysine 27 (H3K27me3) at the genome-wide level during the leaf-to-callus transition in peach. Overall, mCG and mCHH were predominant at the genome-wide level and mCG was predominant in genic regions. H3K27me3 deposition was mainly detected in the gene body and at the TSS site, and GAGA repetitive sequences were prone to recruit H3K27me3 modification. H3K27me3 methylation was negatively correlated with gene expression. In vitro culture of leaf explants was accompanied by DNA hypomethylation and H3K27me3 demethylation, which could activate auxin- and cytokinin-related regulators to induce callus development. The DNA methylation inhibitor 5-azacytidine could significantly increase callus development, while the H3K27me3 demethylase inhibitor GSK-J4 dramatically reduced callus development. These results demonstrate the roles of DNA methylation and H3K27me3 modification in mediating chromatin status during callus development. Our study provides new insights into the epigenetic mechanisms through which differentiated cells acquire proliferative competence to induce callus development in plants.
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Affiliation(s)
- Beibei Zheng
- CAS Key Laboratory of Plant Germplasm Enhancement and Specialty Agriculture, Wuhan Botanical Garden, The Innovative Academy of Seed Design of Chinese Academy of Sciences, Wuhan 430074, China
- Hubei Hongshan Laboratory, Wuhan 430070, China
| | - Jingjing Liu
- CAS Key Laboratory of Plant Germplasm Enhancement and Specialty Agriculture, Wuhan Botanical Garden, The Innovative Academy of Seed Design of Chinese Academy of Sciences, Wuhan 430074, China
- University of Chinese Academy of Sciences, 19A Yuquanlu, Beijing 100049, China
| | - Anqi Gao
- CAS Key Laboratory of Plant Germplasm Enhancement and Specialty Agriculture, Wuhan Botanical Garden, The Innovative Academy of Seed Design of Chinese Academy of Sciences, Wuhan 430074, China
- University of Chinese Academy of Sciences, 19A Yuquanlu, Beijing 100049, China
| | - Xiaomei Chen
- CAS Key Laboratory of Plant Germplasm Enhancement and Specialty Agriculture, Wuhan Botanical Garden, The Innovative Academy of Seed Design of Chinese Academy of Sciences, Wuhan 430074, China
- University of Chinese Academy of Sciences, 19A Yuquanlu, Beijing 100049, China
| | - Lingling Gao
- CAS Key Laboratory of Plant Germplasm Enhancement and Specialty Agriculture, Wuhan Botanical Garden, The Innovative Academy of Seed Design of Chinese Academy of Sciences, Wuhan 430074, China
- University of Chinese Academy of Sciences, 19A Yuquanlu, Beijing 100049, China
| | - Liao Liao
- CAS Key Laboratory of Plant Germplasm Enhancement and Specialty Agriculture, Wuhan Botanical Garden, The Innovative Academy of Seed Design of Chinese Academy of Sciences, Wuhan 430074, China
- Hubei Hongshan Laboratory, Wuhan 430070, China
| | - Binwen Luo
- CAS Key Laboratory of Plant Germplasm Enhancement and Specialty Agriculture, Wuhan Botanical Garden, The Innovative Academy of Seed Design of Chinese Academy of Sciences, Wuhan 430074, China
- University of Chinese Academy of Sciences, 19A Yuquanlu, Beijing 100049, China
| | - Collins Otieno Ogutu
- CAS Key Laboratory of Plant Germplasm Enhancement and Specialty Agriculture, Wuhan Botanical Garden, The Innovative Academy of Seed Design of Chinese Academy of Sciences, Wuhan 430074, China
- Hubei Hongshan Laboratory, Wuhan 430070, China
| | - Yuepeng Han
- Corresponding author. E-mail:
Equal contribution
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Yang J, Hu Y, Zhang B, Liang X, Li X. The JMJD Family Histone Demethylases in Crosstalk Between Inflammation and Cancer. Front Immunol 2022; 13:881396. [PMID: 35558079 PMCID: PMC9090529 DOI: 10.3389/fimmu.2022.881396] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 03/23/2022] [Indexed: 02/05/2023] Open
Abstract
Inflammation has emerged as a key player in regulating cancer initiation, progression, and therapeutics, acting as a double edged sword either facilitating cancer progression and therapeutic resistance or inducing anti-tumor immune responses. Accumulating evidence has linked the epigenetic modifications of histones to inflammation and cancer, and histone modifications-based strategies have shown promising therapeutic potentials against cancer. The jumonji C domain-containing (JMJD) family histone demethylases have exhibited multiple regulator functions in inflammatory processes and cancer development, and a number of therapeutic strategies targeting JMJD histone demethylases to modulate inflammatory cells and their products have been successfully evaluated in clinical or preclinical tumor models. This review summarizes current understanding of the functional roles and mechanisms of JMJD histone demethylases in crosstalk between inflammation and cancer, and highlights recent clinical and preclinical progress on harnessing the JMJD histone demethylases to regulate cancer-related inflammation for future cancer therapeutics.
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Affiliation(s)
- Jia Yang
- Department of Gynecology and Obstetrics and Pediatric Nephrology Nursing, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Yuan Hu
- Department of Gynecology and Obstetrics and Pediatric Nephrology Nursing, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Binjing Zhang
- State Key Laboratory of Oral Disease, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xiao Liang
- Department of Gynecology and Obstetrics and Pediatric Nephrology Nursing, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Xin Li
- State Key Laboratory of Oral Disease, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Jauch-Speer SL, Herrera-Rivero M, Ludwig N, Véras De Carvalho BC, Martens L, Wolf J, Imam Chasan A, Witten A, Markus B, Schieffer B, Vogl T, Rossaint J, Stoll M, Roth J, Fehler O. C/EBPδ-induced epigenetic changes control the dynamic gene transcription of S100a8 and S100a9. eLife 2022; 11:75594. [PMID: 35543413 PMCID: PMC9122501 DOI: 10.7554/elife.75594] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 05/06/2022] [Indexed: 11/25/2022] Open
Abstract
The proinflammatory alarmins S100A8 and S100A9 are among the most abundant proteins in neutrophils and monocytes but are completely silenced after differentiation to macrophages. The molecular mechanisms of the extraordinarily dynamic transcriptional regulation of S100a8 and S100a9 genes, however, are only barely understood. Using an unbiased genome-wide CRISPR/Cas9 knockout (KO)-based screening approach in immortalized murine monocytes, we identified the transcription factor C/EBPδ as a central regulator of S100a8 and S100a9 expression. We showed that S100A8/A9 expression and thereby neutrophil recruitment and cytokine release were decreased in C/EBPδ KO mice in a mouse model of acute lung inflammation. S100a8 and S100a9 expression was further controlled by the C/EBPδ antagonists ATF3 and FBXW7. We confirmed the clinical relevance of this regulatory network in subpopulations of human monocytes in a clinical cohort of cardiovascular patients. Moreover, we identified specific C/EBPδ-binding sites within S100a8 and S100a9 promoter regions, and demonstrated that C/EBPδ-dependent JMJD3-mediated demethylation of H3K27me3 is indispensable for their expression. Overall, our work uncovered C/EBPδ as a novel regulator of S100a8 and S100a9 expression. Therefore, C/EBPδ represents a promising target for modulation of inflammatory conditions that are characterized by S100a8 and S100a9 overexpression.
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Affiliation(s)
| | | | - Nadine Ludwig
- Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany
| | | | - Leonie Martens
- Institute of Immunology, University of Münster, Münster, Germany
| | - Jonas Wolf
- Institute of Immunology, University of Münster, Münster, Germany
| | | | - Anika Witten
- Department of Genetic Epidemiology, University of Münster, Münster, Germany
| | - Birgit Markus
- Clinic for Cardiology, Angiology and Internal Intensive Medicine, University Hospital Marburg, Marburg, Germany
| | - Bernhard Schieffer
- Clinic for Cardiology, Angiology and Internal Intensive Medicine, University Hospital Marburg, Marburg, Germany
| | - Thomas Vogl
- Institute of Immunology, University of Münster, Münster, Germany
| | - Jan Rossaint
- Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany
| | - Monika Stoll
- Department of Genetic Epidemiology, University of Münster, Münster, Germany
| | - Johannes Roth
- Institute of Immunology, University of Münster, Münster, Germany
| | - Olesja Fehler
- Institute of Immunology, University of Münster, Münster, Germany
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Sanchez A, Penault-Llorca F, Bignon YJ, Guy L, Bernard-Gallon D. Effects of GSK-J4 on JMJD3 Histone Demethylase in Mouse Prostate Cancer Xenografts. Cancer Genomics Proteomics 2022; 19:339-349. [PMID: 35430567 DOI: 10.21873/cgp.20324] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/04/2022] [Accepted: 02/10/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND/AIM Histone methylation status is required to control gene expression. H3K27me3 is an epigenetic tri-methylation modification to histone H3 controlled by the demethylase JMJD3. JMJD3 is dysregulated in a wide range of cancers and has been shown to control the expression of a specific growth-modulatory gene signature, making it an interesting candidate to better understand prostate tumor progression in vivo. This study aimed to identify the impact of JMJD3 inhibition by its inhibitor, GSK4, on prostate tumor growth in vivo. MATERIALS AND METHODS Prostate cancer cell lines were implanted into Balb/c nude male mice. The effects of the selective JMJD3 inhibitor GSK-J4 on tumor growth were analyzed by bioluminescence assays and H3K27me3-regulated changes in gene expression were analyzed by ChIP-qPCR and RT-qPCR. RESULTS JMJD3 inhibition contributed to an increase in tumor growth in androgen-independent (AR-) xenografts and a decrease in androgen-dependent (AR+). GSK-J4 treatment modulated H3K27me3 enrichment on the gene panel in DU-145-luc xenografts while it had little effect on PC3-luc and no effect on LNCaP-luc. Effects of JMJD3 inhibition affected the panel gene expression. CONCLUSION JMJD3 has a differential effect in prostate tumor progression according to AR status. Our results suggest that JMJD3 is able to play a role independently of its demethylase function in androgen-independent prostate cancer. The effects of GSK-J4 on AR+ prostate xenografts led to a decrease in tumor growth.
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Affiliation(s)
- Anna Sanchez
- Department of Oncogenetics, Centre Jean Perrin, Clermont-Ferrand, France.,INSERM U 1240 Molecular Imagery and Theranostic Strategies (IMoST), Clermont-Ferrand, France
| | - Frédérique Penault-Llorca
- INSERM U 1240 Molecular Imagery and Theranostic Strategies (IMoST), Clermont-Ferrand, France.,Department of Biopathology, Centre Jean Perrin, Clermont-Ferrand, France
| | - Yves-Jean Bignon
- Department of Oncogenetics, Centre Jean Perrin, Clermont-Ferrand, France.,INSERM U 1240 Molecular Imagery and Theranostic Strategies (IMoST), Clermont-Ferrand, France
| | - Laurent Guy
- INSERM U 1240 Molecular Imagery and Theranostic Strategies (IMoST), Clermont-Ferrand, France.,Department of Urology, Gabriel Montpied Hospital, Clermont-Ferrand, France
| | - Dominique Bernard-Gallon
- Department of Oncogenetics, Centre Jean Perrin, Clermont-Ferrand, France; .,INSERM U 1240 Molecular Imagery and Theranostic Strategies (IMoST), Clermont-Ferrand, France
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Whiteley SL, Wagner S, Holleley CE, Deveson IW, Marshall Graves JA, Georges A. Truncated jarid2 and kdm6b transcripts are associated with temperature-induced sex reversal during development in a dragon lizard. SCIENCE ADVANCES 2022; 8:eabk0275. [PMID: 35442724 PMCID: PMC9020659 DOI: 10.1126/sciadv.abk0275] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 03/04/2022] [Indexed: 05/23/2023]
Abstract
Sex determination and differentiation in reptiles are complex. In the model species, Pogona vitticeps, high incubation temperature can cause male to female sex reversal. To elucidate the epigenetic mechanisms of thermolabile sex, we used an unbiased genome-wide assessment of intron retention during sex reversal. The previously implicated chromatin modifiers (jarid2 and kdm6b) were two of three genes to display sex reversal-specific intron retention. In these species, embryonic intron retention resulting in C-terminally truncated jarid2 and kdm6b isoforms consistently occurs at low temperatures. High-temperature sex reversal is uniquely characterized by a high prevalence of N-terminally truncated isoforms of jarid2 and kdm6b, which are not present at low temperatures, or in two other reptiles with temperature-dependent sex determination. This work verifies that chromatin-modifying genes are involved in highly conserved temperature responses and can also be transcribed into isoforms with new sex-determining roles.
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Affiliation(s)
- Sarah L. Whiteley
- Institute for Applied Ecology, University of Canberra, Bruce, Australia
- Australian National Wildlife Collection, CSIRO National Research Collections Australia, Canberra, Australia
| | - Susan Wagner
- Institute for Applied Ecology, University of Canberra, Bruce, Australia
| | - Clare E. Holleley
- Australian National Wildlife Collection, CSIRO National Research Collections Australia, Canberra, Australia
| | - Ira W. Deveson
- Garvan Institute of Medical Research, Sydney, Australia
- St. Vincent’s Clinical School, UNSW, Sydney, Australia
| | | | - Arthur Georges
- Institute for Applied Ecology, University of Canberra, Bruce, Australia
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Kamiya T, Yamaguchi Y, Oka M, Hara H. Combined action of FOXO1 and superoxide dismutase 3 promotes MDA-MB-231 cell migration. Free Radic Res 2022; 56:106-114. [PMID: 35271779 DOI: 10.1080/10715762.2022.2049770] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Superoxide dismutase 3 (SOD3), one of SOD isozymes, maintains extracellular redox homeostasis through the dismutation reaction of superoxide. Loss of SOD3 in tumor cells induces oxidative stress and exacerbates tumor progression; however, interestingly, overexpression of SOD3 also promotes cell proliferation through the production of hydrogen peroxide. In this study, we investigated the functional role of SOD3 in human breast cancer MDA-MB-231 cell migration and the molecular mechanisms involved in high expression of SOD3 in MDA-MB-231 cells and human monocytic THP-1 cells. The level of histone H3 trimethylation at lysine 27 (H3K27me3), a marker of gene silencing, was decreased in 12-O-tetra-decanoylphorbol-13-acetate (TPA)-treated THP-1 cells. Also, that reduction was observed within the SOD3 promoter region. We then investigated the involvement of H3K27 demethylase JMJD3 in SOD3 induction. The induction of SOD3 and the reduction of H3K27me3 were inhibited in the presence of JMJD3 inhibitor, GSK-J4. Additionally, it was first determined that the knockdown of the transcription factor forkhead box O1 (FOXO1) significantly suppressed TPA-elicited SOD3 induction. FOXO1-mediated SOD3 downregulation was also observed in MDA-MB-231 cells, and knockdown of FOXO1 and SOD3 suppressed cell migration. Our results provide a novel insight into epigenetic regulation of SOD3 expression in tumor-associated cells, and high expression of FOXO1 and SOD3 would participate in the migration of MDA-MB-231 cells.
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Affiliation(s)
- Tetsuro Kamiya
- Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan
| | - Yuji Yamaguchi
- Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan
| | - Manami Oka
- Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan
| | - Hirokazu Hara
- Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan
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Yıldırım-Buharalıoğlu G. Lysine Demethylase 6B Regulates Prostate Cancer Cell Proliferation by Controlling c-MYC Expression. Mol Pharmacol 2022; 101:106-119. [PMID: 34862309 DOI: 10.1124/molpharm.121.000372] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 11/29/2021] [Indexed: 11/22/2022] Open
Abstract
Elevated expression of lysine demethylase 6A (KDM6A) and lysine demethylase 6B (KDM6B) has been reported in prostate cancer (PCa). However, the mechanism underlying the specific role of KDM6A/B in PCa is still fragmentary. Here, we report novel KDM6A/B downstream targets involved in controlling PCa cell proliferation. KDM6A and KDM6B mRNAs were higher in prostate adenocarcinoma, lymph node metastatic site (LNCaP) but not in prostate adenocarcinoma, bone metastatic site (PC3) and prostate adenocarcinoma, brain metastatic site (DU145) cells. Higher KDM6A mRNA was confirmed at the protein level. A metastasis associated gene focused oligonucleotide array was performed to identify KDM6A/B dependent genes in LNCaP cells treated with a KDM6 family selective inhibitor, ethyl-3-(6-(4,5-dihydro-1H-benzo[d]azepin-3(2H)-yl)-2-(pyridin-2-yl)pyrimidin-4-ylamino)propanoate (GSK-J4). This identified five genes [V-myc myelocytomatosis viral oncogene homolog (avian) (c-MYC), neurofibromin 2 (merlin) (NF2), C-terminal binding protein 1 (CTBP1), EPH receptor B2 (EPHB2), and plasminogen activator urokinase receptor (PLAUR)] that were decreased more than 50% by GSK-J4, and c-MYC was the most downregulated gene. Array data were validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR), which detected a reduction in c-MYC steady state mRNA and prespliced mRNA, indicative of transcriptional repression of c-MYC gene expression. Furthermore, c-MYC protein was also decreased by GSK-J4. Importantly, GSK-J4 reduced mRNA and protein levels of c-MYC target gene, cyclinD1 (CCND1). Silencing of KDM6A/B with small interfering RNA (siRNA) confirmed that expression of both c-MYC and CCND1 are dependent on KDM6B. Phosphorylated retinoblastoma (pRb), a marker of G1 to S-phase transition, was decreased by GSK-J4 and KDM6B silencing. GSK-J4 treatment resulted in a decrease in cell proliferation and cell number, detected by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay and conventional cell counting, respectively. Consequently, we conclude that KDM6B controlling c-MYC, CCND1, and pRb contribute regulation of PCa cell proliferation, which represents KDM6B as a promising epigenetic target for the treatment of advanced PCa. SIGNIFICANCE STATEMENT: Lysine demethylase 6A (KDM6A) and 6B (KDM6B) were upregulated in prostate cancer (PCa). We reported novel KDM6A/B downstream targets controlling proliferation. Amongst 84 metastasis associated genes, V-myc myelocytomatosis viral oncogene homolog (avian) (c-MYC) was the most inhibited gene by KDM6 inhibitor, ethyl-3-(6-(4,5-dihydro-1H-benzo[d]azepin-3(2H)-yl)-2-(pyridin-2-yl)pyrimidin-4-ylamino)propanoate (GSK-J4). This was accompanied by decreased c-MYC targets, cyclinD1 (CCND1) and phosphorylated retinoblastoma (pRb), which were KDM6B dependent. GSK-J4 decreased proliferation and cell counting. We conclude that KDM6B controlling c-MYC, CCND1, and pRb contribute regulation of PCa proliferation.
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Kamiya T. Copper in the tumor microenvironment and tumor metastasis. J Clin Biochem Nutr 2022; 71:22-28. [PMID: 35903604 PMCID: PMC9309082 DOI: 10.3164/jcbn.22-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 03/12/2022] [Indexed: 11/22/2022] Open
Abstract
Copper (Cu), an essential micronutrient, plays an essential role in several physiological processes, including cell proliferation and angiogenesis; however, its dysregulation induces oxidative stress and inflammatory responses. Significant Cu accumulation is observed in several tumor tissues. The bioavailability of intracellular Cu is tightly controlled by Cu transporters, including Cu transporter 1 (CTR1) and Cu-transporting P-type ATPase α and β (ATP7A and ATP7B), and Cu chaperones, including Cu chaperone for superoxide dismutase 1 (CCS) and antioxidant-1 (Atox-1). In several tumor tissues, these abnormalities that induce intracellular Cu accumulation are involved in tumor progression. In addition, functional disturbance in Cu-containing secretory enzymes, such as superoxide dismutase 3 (SOD3), and lysyl oxidase enzymes (LOX and LOXL1–4) with abnormal Cu dynamics plays a key role in tumor metastasis. For example, the loss of SOD3 in tumor tissues induces oxidative stress, which promotes neovascularization and epithelial-to-mesenchymal transition (EMT). LOX promotes collagen crosslinking, which functions in the metastatic niche formation. Accordingly, restricted Cu regulation may be a novel strategy for the inhibition of tumor metastasis. However, it is unclear how these Cu disturbances occur in tumor tissues and the exact molecular mechanisms underlying Cu secretory enzymes. In this review article, I discuss the role of Cu transporters, Cu chaperones, and Cu-containing secretory enzymes in tumor progression to better understand the role of Cu homeostasis in tumor tissues.
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Affiliation(s)
- Tetsuro Kamiya
- Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University
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Van de Walle T, Cools L, Mangelinckx S, D'hooghe M. Recent contributions of quinolines to antimalarial and anticancer drug discovery research. Eur J Med Chem 2021; 226:113865. [PMID: 34655985 DOI: 10.1016/j.ejmech.2021.113865] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 09/01/2021] [Accepted: 09/20/2021] [Indexed: 12/28/2022]
Abstract
Quinoline, a privileged scaffold in medicinal chemistry, has always been associated with a multitude of biological activities. Especially in antimalarial and anticancer research, quinoline played (and still plays) a central role, giving rise to the development of an array of quinoline-containing pharmaceuticals in these therapeutic areas. However, both diseases still affect millions of people every year, pointing to the necessity of new therapies. Quinolines have a long-standing history as antimalarial agents, but established quinoline-containing antimalarial drugs are now facing widespread resistance of the Plasmodium parasite. Nevertheless, as evidenced by a massive number of recent literature contributions, they are still of great value for future developments in this field. On the other hand, the number of currently approved anticancer drugs containing a quinoline scaffold are limited, but a strong increase and interest in quinoline compounds as potential anticancer agents can be seen in the last few years. In this review, a literature overview of recent contributions made by quinoline-containing compounds as potent antimalarial or anticancer agents is provided, covering publications between 2018 and 2020.
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Affiliation(s)
- Tim Van de Walle
- SynBioC Research Group, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000, Ghent, Belgium
| | - Lore Cools
- SynBioC Research Group, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000, Ghent, Belgium
| | - Sven Mangelinckx
- SynBioC Research Group, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000, Ghent, Belgium
| | - Matthias D'hooghe
- SynBioC Research Group, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000, Ghent, Belgium.
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D'Oto A, Fang J, Jin H, Xu B, Singh S, Mullasseril A, Jones V, Abu-Zaid A, von Buttlar X, Cooke B, Hu D, Shohet J, Murphy AJ, Davidoff AM, Yang J. KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma. Nat Commun 2021; 12:7204. [PMID: 34893606 PMCID: PMC8664842 DOI: 10.1038/s41467-021-27502-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 11/18/2021] [Indexed: 12/12/2022] Open
Abstract
The H3K27me2/me3 histone demethylase KDM6B is essential to neuroblastoma cell survival. However, the mechanism of KDM6B action remains poorly defined. We demonstrate that inhibition of KDM6B activity 1) reduces the chromatin accessibility of E2F target genes and MYCN, 2) selectively leads to an increase of H3K27me3 but a decrease of the enhancer mark H3K4me1 at the CTCF and BORIS binding sites, which may, consequently, disrupt the long-range chromatin interaction of MYCN and E2F target genes, and 3) phenocopies the transcriptome induced by the specific CDK4/6 inhibitor palbociclib. Overexpression of CDK4/6 or Rb1 knockout confers neuroblastoma cell resistance to both palbociclib and the KDM6 inhibitor GSK-J4. These data indicate that KDM6B promotes an oncogenic CDK4/6-pRB-E2F pathway in neuroblastoma cells via H3K27me3-dependent enhancer-promoter interactions, providing a rationale to target KDM6B for high-risk neuroblastoma. The histone demethylase KDM6B is reported to be essential for neuroblastoma cell survival. Here the authors show that KDM6B regulates CDK4/6-pRB-E2F pathway through H3K27me3-dependent enhancer-promoter interactions in neuroblastoma.
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Affiliation(s)
- Alexandra D'Oto
- Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Jie Fang
- Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Hongjian Jin
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Beisi Xu
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Shivendra Singh
- Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Anoushka Mullasseril
- Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Victoria Jones
- Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Ahmed Abu-Zaid
- Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Xinyu von Buttlar
- Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Bailey Cooke
- Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Dongli Hu
- Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Jason Shohet
- Department of Pediatrics, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA
| | - Andrew J Murphy
- Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Andrew M Davidoff
- Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
| | - Jun Yang
- Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
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Whiteley S, McCuaig RD, Holleley CE, Rao S, Georges A. Dynamics of epigenetic modifiers and environmentally sensitive proteins in a reptile with temperature induced sex reversal. Biol Reprod 2021; 106:132-144. [PMID: 34849582 DOI: 10.1093/biolre/ioab217] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/25/2021] [Indexed: 12/23/2022] Open
Abstract
The mechanisms by which sex is determined, and how a sexual phenotype is stably maintained during adulthood, has been the focus of vigorous scientific inquiry. Resources common to the biomedical field (automated staining and imaging platforms) were leveraged to provide the first immunofluorescent data for a reptile species with temperature induced sex reversal. Two four-plex immunofluorescent panels were explored across three sex classes (sex reversed ZZf females, normal ZWf females, and normal ZZm males). One panel was stained for chromatin remodelling genes JARID2 and KDM6B, and methylation marks H3K27me3, and H3K4me3 (Jumonji Panel). The other CaRe panel stained for environmental response genes CIRBP and RelA, and H3K27me3 and H3K4me3. Our study characterised tissue specific expression and cellular localisation patterns of these proteins and histone marks, providing new insights to the molecular characteristics of adult gonads in a dragon lizard Pogona vitticeps. The confirmation that mammalian antibodies cross react in P. vitticeps paves the way for experiments that can take advantage of this new immunohistochemical resource to gain a new understanding of the role of these proteins during embryonic development, and most importantly for P. vitticeps, the molecular underpinnings of sex reversal.
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Affiliation(s)
- Sarah Whiteley
- Institute for Applied Ecology, University of Canberra, Australia.,Australian National Wildlife Collection CSIRO National Research Collections Australia, Canberra, Australia
| | - Robert D McCuaig
- Gene Regulation and Translational Medicine Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Clare E Holleley
- Australian National Wildlife Collection CSIRO National Research Collections Australia, Canberra, Australia
| | - Sudha Rao
- Gene Regulation and Translational Medicine Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Arthur Georges
- Institute for Applied Ecology, University of Canberra, Australia
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Li L, Bai L, Yang K, Zhang J, Gao Y, Jiang M, Yang Y, Zhang X, Wang L, Wang X, Qiao Y, Xu JT. KDM6B epigenetically regulated-interleukin-6 expression in the dorsal root ganglia and spinal dorsal horn contributes to the development and maintenance of neuropathic pain following peripheral nerve injury in male rats. Brain Behav Immun 2021; 98:265-282. [PMID: 34464689 DOI: 10.1016/j.bbi.2021.08.231] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 08/17/2021] [Accepted: 08/21/2021] [Indexed: 12/20/2022] Open
Abstract
The lysine specific demethylase 6B (KDM6B) has been implicated as a coregulator in the expression of proinflammatory mediators, and in the pathogenesis of inflammatory and arthritic pain. However, the role of KDM6B in neuropathic pain has yet to be studied. In the current study, the neuropathic pain was determined by assessing the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) following lumbar 5 spinal nerve ligation (SNL) in male rats. Immunohistochemistry, Western blotting, qRT-PCR, and chromatin immunoprecipitation (ChIP)-PCR assays were performed to investigate the underlying mechanisms. Our results showed that SNL led to a significant increase in KDM6B mRNA and protein in the ipsilateral L4/5 dorsal root ganglia (DRG) and spinal dorsal horn; and this increase correlated a markedly reduction in the level of H3K27me3 methylation in the same tissue. Double immunofluorescence staining revealed that the KDM6B expressed in myelinated A- and unmyelinated C-fibers in the DRG; and located in neuronal cells, astrocytes, and microglia in the dorsal horn. Behavioral data showed that SNL-induced mechanical allodynia and thermal hyperalgesia were impaired by the treatment of prior to i.t. injection of GSK-J4, a specific inhibitor of KDM6B, or KDM6B siRNA. Both microinjection of AAV2-EGFP-KDM6B shRNA in the lumbar 5 dorsal horn and sciatic nerve, separately, alleviated the neuropathic pain following SNL. The established neuropathic pain was also partially attenuated by repeat i.t. injections of GSK-J4 or KDM6B siRNA, started on day 7 after SNL. SNL also resulted in a remarkable increased expression of interleukin-6 (IL-6) in the DRG and dorsal horn. But this increase was dramatically inhibited by i.t. injection of GSK-J4 and KDM6B siRNA; and suppressed by prior to microinjection of AAV2-EGFP-KDM6B shRNA in the dorsal horn and sciatic nerve. Results of ChIP-PCR assay showed that SNL-induced enhanced binding of STAT3 with IL-6 promoter was inhibited by prior to i.t. injection of GSK-J4. Meanwhile, the level of H3K27me3 methylation was also decreased by the treatment. Together, our results indicate that SNL-induced upregulation of KDM6B via demethylating H3K27me3 facilitates the binding of STAT3 with IL-6 promoter, and subsequently mediated-increase in the expression of IL-6 in the DRG and dorsal horn contributes to the development and maintenance of neuropathic pain. Targeting KDM6B might a promising therapeutic strategy to treatment of chronic pain.
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Affiliation(s)
- Liren Li
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Liying Bai
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China; Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital, Zhengzhou University, 1 Jianshe East Road, Zhengzhou 450052, China
| | - Kangli Yang
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China; Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital, Zhengzhou University, 1 Jianshe East Road, Zhengzhou 450052, China
| | - Jian Zhang
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Yan Gao
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China; Neuroscience Research Institute, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Mingjun Jiang
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Yin Yang
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Xuan Zhang
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Li Wang
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Xueli Wang
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Yiming Qiao
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Ji-Tian Xu
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China; Neuroscience Research Institute, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China.
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The progress of research on histone methylation in ischemic stroke pathogenesis. J Physiol Biochem 2021; 78:1-8. [PMID: 34472033 DOI: 10.1007/s13105-021-00841-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 08/16/2021] [Indexed: 10/20/2022]
Abstract
Stroke, also known as cerebral stroke or cerebrovascular accident, refers to acute ischemic or hemorrhagic encephalopathy caused by a disturbance to cerebral blood flow. Ischemic stroke is the most common type of cerebral stroke, accounting for approximately 80% of the total incidence of clinical stroke. High morbidity, disability, and mortality rates place heavy burdens on the families of patients and society. An increasing number of studies have shown that histone modification plays an important role in the pathogenesis of ischemic stroke, but most studies on histone modification focus on acetylation, and studies on the role of histone methylation in the pathogenesis of ischemic stroke are limited. Here, we review the role of histone methylation and related histone methyltransferase (HMT) inhibitors in the pathogenesis of ischemic stroke and related HMT inhibitors in the treatment of ischemic stroke, which may open up a new avenue to the study of ischemic stroke.
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Yang F, Lin J, Chen W. Post-translational modifications in T cells in systemic erythematosus lupus. Rheumatology (Oxford) 2021; 60:2502-2516. [PMID: 33512488 DOI: 10.1093/rheumatology/keab095] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 01/21/2021] [Accepted: 01/23/2021] [Indexed: 02/07/2023] Open
Abstract
Systemic erythematosus lupus (SLE) is a classic autoimmune disease characterized by multiple autoantibodies and immune-mediated tissue damage. The aetiology of this disease is still unclear. A new drug, belimumab, which acts against the B-lymphocyte stimulator (BLyS), can effectively improve the condition of SLE patients, but it cannot resolve all SLE symptoms. The discovery of novel, precise therapeutic targets is urgently needed. It is well known that abnormal T-cell function is one of the most crucial factors contributing to the pathogenesis of SLE. Protein post-translational modifications (PTMs), including phosphorylation, glycosylation, acetylation, methylation, ubiquitination and SUMOylation have been emphasized for their roles in activating protein activity, maintaining structural stability, regulating protein-protein interactions and mediating signalling pathways, in addition to other biological functions. Summarizing the latest data in this area, this review focuses on the potential roles of diverse PTMs in regulating T-cell function and signalling pathways in SLE pathogenesis, with the goal of identifying new targets for SLE therapy.
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Affiliation(s)
- Fan Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang, China
| | - Jin Lin
- Division of Rheumatology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Weiqian Chen
- Division of Rheumatology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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