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1
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Luo X, Tang N, Ren Y, Li J, Zhu H, Wu S, Ding Z. Single-cell multi-dimensional data analysis decodes RNF19A-mediated drug resistance in rheumatoid arthritis fibroblast-like synoviocytes: mechanisms and biological insights. Cell Mol Life Sci 2025; 82:180. [PMID: 40293542 PMCID: PMC12037462 DOI: 10.1007/s00018-025-05707-8] [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: 11/10/2024] [Revised: 03/16/2025] [Accepted: 04/08/2025] [Indexed: 04/30/2025]
Abstract
Rheumatoid arthritis (RA) is a prevalent autoimmune disease, affecting approximately 1% of the global population. Methotrexate (MTX) is the most widely prescribed drug for RA treatment; however, its efficacy is often limited, with resistance frequently observed. Fibroblast-like synoviocytes (FLS) play a pivotal role in RA progression and are closely linked to drug resistance, although the underlying mechanisms remain poorly understood. In this study, we conducted a comprehensive analysis of public single-cell transcriptomics data from osteoarthritis and rheumatoid arthritis synovial tissues, identifying RNF19A as a gene potentially associated with RA resistance in FLS. Our findings indicate that RNF19A is significantly overexpressed in drug-resistant FLS and is closely associated with the dysregulation of FLS proliferation, migration, invasion, and apoptosis. Furthermore, we demonstrated that RNF19A promotes functional disruption in FLS by ubiquitinating and degrading MKP-1, thereby activating the MAPK signaling pathway. This activation also facilitates the nuclear translocation of ZBTB20, an upstream transcription factor of RNF19A, which further enhances RNF19A transcription. This biological process creates a positive feedback loop in FLS, contributing to RA resistance-a mechanism that was also validated in vivo. In summary, this study is the first to underscore the crucial role of RNF19A in mediating drug resistance in RA FLS, elucidating the underlying biological processes, and providing novel insights into RA pathogenesis, thereby offering a new experimental foundation for RA drug development.
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Affiliation(s)
- Xin Luo
- Department of Orthopedics, Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Ning Tang
- Department of Orthopedics, Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Yijun Ren
- Department of Neurology, Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Jingchen Li
- Department of Food Engineering, College of Life Science, Dalian Minzu University, Dalian, Liaoning, China
| | - Huancheng Zhu
- Lab of Research and Engineering of Cell Therapy Technology, Hangzhou Institute of Medicine Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Song Wu
- Department of Orthopedics, Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zhiyu Ding
- Department of Orthopedics, Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
- Lab of Research and Engineering of Cell Therapy Technology, Hangzhou Institute of Medicine Chinese Academy of Sciences, Hangzhou, Zhejiang, China.
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2
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Zhao Y, Gai C, Yu S, Song Y, Gu B, Luo Q, Wang X, Hu Q, Liu W, Liu D, Wang Z. Liposomes-Loaded miR-9-5p Alleviated Hypoxia-Ischemia-Induced Mitochondrial Oxidative Stress by Targeting ZBTB20 to Inhibiting Nrf2/Keap1 Interaction in Neonatal Mice. Antioxid Redox Signal 2025; 42:512-528. [PMID: 39869050 DOI: 10.1089/ars.2024.0640] [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] [Indexed: 01/28/2025]
Abstract
Aims: Hypoxia ischemia (HI) is a leading cause of cerebral palsy and long-term neurological sequelae in infants. Given that mitochondrial dysfunction in neurons contributes to HI brain damage, this study aimed to investigate the regulatory role of miR-9-5p in mitochondrial function following HI injury. Results: Overexpression of miR-9-5p in HI mice or H2O2-exposed PC12 cells suppressed neuronal injury, associated with increased mitochondrial copy number, normalizing mitochondrial membrane potential, improved nuclear factor-erythroid factor 2-related factor 2 (Nrf2) activation, and downregulation of Keap1. This was mediated, in part, through the ability of this miR-9-5p to bind and regulate the transcriptional activity of zinc finger and BTB domain-containing protein 20 (ZBTB20). Further study suggested that the knockdown of ZBTB20 exerts neuroprotection by inhibiting Nrf2/Keap1 interaction to promote the translocation of Nrf2 from the cytoplasm to the nucleus and the consequent expression of antioxidant proteins. Notably, the protective effects of miR-9-5p overexpression against HI-induced mitochondrial damage were reversed by the Nrf2 inhibitor ML385. Finally, the utilization of liposomes for the delivery of miR-9-5p (miR-9-5p@Lip) presents a promising therapeutic strategy for the treatment of HI injury. Innovation: miR-9-5p is a potential therapeutic agent for ischemic stroke through its modulation of the ZBTB20/Nrf2/Keap1 signaling pathway, influencing mitochondrial function and antioxidant response. Furthermore, the use of liposomal delivery for miR-9-5p offers a promising therapeutic strategy for HI injury. Conclusion: Overexpression of miR-9-5p protects against cerebral HI injury by modulating mitochondrial function through the ZBTB20/Nrf2/Keap1 signaling pathway. Antioxid. Redox Signal. 42, 512-528. [Figure: see text].
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Affiliation(s)
- Yijing Zhao
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Chengcheng Gai
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Shuwen Yu
- Department of Medical Psychology and Ethics, School of Basic Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Yan Song
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Bing Gu
- Department of Medical Psychology and Ethics, School of Basic Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Qian Luo
- Department of Medical Psychology and Ethics, School of Basic Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Xixi Wang
- Department of Medical Psychology and Ethics, School of Basic Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Quan Hu
- The Affiliated Taian City Central Hospital of Qingdao University, Taian, People's Republic of China
| | - Weiyang Liu
- Jinan Xicheng Experimental High School, Jinan, People's Republic of China
| | - Dexiang Liu
- Department of Medical Psychology and Ethics, School of Basic Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Zhen Wang
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
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Ma S, Wang L, Zhang J, Geng L, Yang J. The role of transcriptional and epigenetic modifications in astrogliogenesis. PeerJ 2024; 12:e18151. [PMID: 39314847 PMCID: PMC11418818 DOI: 10.7717/peerj.18151] [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: 05/10/2024] [Accepted: 08/31/2024] [Indexed: 09/25/2024] Open
Abstract
Astrocytes are widely distributed and play a critical role in the central nervous system (CNS) of the human brain. During the development of CNS, astrocytes provide essential nutritional and supportive functions for neural cells and are involved in their metabolism and pathological processes. Despite the numerous studies that have reported on the regulation of astrogliogenesis at the transcriptional and epigenetic levels, there is a paucity of literature that provides a comprehensive summary of the key factors influencing this process. In this review, we analyzed the impact of transcription factors (e.g., NFI, JAK/STAT, BMP, and Ngn2), DNA methylation, histone acetylation, and noncoding RNA on astrocyte behavior and the regulation of astrogliogenesis, hope it enhances our comprehension of the mechanisms underlying astrogliogenesis and offers a theoretical foundation for the treatment of patients with neurological diseases.
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Affiliation(s)
- Shuangping Ma
- Institutes of Health Central Plains, Tissue Engineering and Regenerative Clinical Medicine Center, Xinxiang Medical University, Xinxiang, China
| | - Lei Wang
- Institutes of Health Central Plains, Tissue Engineering and Regenerative Clinical Medicine Center, Xinxiang Medical University, Xinxiang, China
| | - Junhe Zhang
- Institutes of Health Central Plains, Tissue Engineering and Regenerative Clinical Medicine Center, Xinxiang Medical University, Xinxiang, China
| | - Lujing Geng
- College of Life Sciences and Technology, Xinxiang Medical University, Xinxiang, China
| | - Junzheng Yang
- Institutes of Health Central Plains, Tissue Engineering and Regenerative Clinical Medicine Center, Xinxiang Medical University, Xinxiang, China
- Guangdong Nephrotic Drug Engineering Technology Research Center, The R&D Center of Drug for Renal Diseases, Consun Pharmaceutical Group, Guangzhou, China
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4
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Duan P, Li B, Zhou Y, Cao H, Chen S, Xing Y. ZBTB20 suppresses tumor growth in glioblastoma through activating the TET1/FAS/caspase‑3 pathway. Oncol Lett 2024; 28:358. [PMID: 38881713 PMCID: PMC11176889 DOI: 10.3892/ol.2024.14491] [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: 07/10/2023] [Accepted: 04/16/2024] [Indexed: 06/18/2024] Open
Abstract
Zinc finger and BTB domain containing 20 (ZBTB20) is a key transcription repressor that regulates multiple physiological and pathophysiological processes. Thus far, the role of ZBTB20 in glioblastoma (GBM), a World Health Organization grade IV glioma, remains unclear. In the present study, the expression profile data of ZBTB20 in GBM tissues from public databases was analyzed. It was found that ZBTB20 expression in GBM tissues was significantly lower than that measured in lower grade glioma tissues. Furthermore, patients with GBM with lower ZBTB20 expression were associated with a shorter overall survival time. Gain- and loss-of-function experiments in GBM cells were also performed. The results demonstrated that ZBTB20 overexpression decreased GBM cell proliferation, while ZBTB20 knockdown significantly enhanced it. Cell cycle analysis showed the ZBTB20 overexpression may have inhibited proliferation through cell cycle arrest at the G2/M phase, while ZBTB20 knockdown increased the percentages of cells in both the S phase and G2/M phase. Ten-eleven translocation 1 (TET1) is an important tumor suppressor involved in the formation of various types of tumor, and it was upregulated in ZBTB20-overexpressing GBM cells. It was further demonstrated that ZBTB20 activated the TET1/FAS/caspase-3 pathway. The results of the present study therefore indicated the potential role of ZBTB20 as a tumor suppressor and therapeutic target for GBM.
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Affiliation(s)
- Ping Duan
- Department of Physiology and Neurobiology, College of Medicine, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Bo Li
- Department of Physiology and Neurobiology, College of Medicine, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Yifan Zhou
- Department of Physiology and Neurobiology, College of Medicine, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Huanhuan Cao
- Department of Physiology and Neurobiology, College of Medicine, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Shiyue Chen
- Department of Physiology and Neurobiology, College of Medicine, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Ying Xing
- Department of Physiology and Neurobiology, College of Medicine, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
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5
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González Maciel A, Rosas López LE, Romero-Velázquez RM, Ramos-Morales A, Ponce-Macotela M, Calderón-Guzmán D, Trujillo-Jiménez F, Alfaro-Rodríguez A, Reynoso-Robles R. Postnatal zinc deficiency due to giardiasis disrupts hippocampal and cerebellar development. PLoS Negl Trop Dis 2024; 18:e0012302. [PMID: 38950061 PMCID: PMC11244800 DOI: 10.1371/journal.pntd.0012302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 07/12/2024] [Accepted: 06/20/2024] [Indexed: 07/03/2024] Open
Abstract
BACKGROUND Giardiasis and zinc deficiency have been identified as serious health problems worldwide. Although Zn depletion is known to occur in giardiasis, no work has investigated whether changes occur in brain structures. METHODS Three groups of gerbils were used: control (1), orogastrically inoculated on day 3 after birth with trophozoites of two isolates of Giardia intestinalis (HGINV/WB) group (2 and 3). Estimates were made at five ages covering: establishment of infection, Giardia population growth, natural parasite clearance and a post-infection age. QuantiChrome zinc assay kit, cresyl violet staining and TUNEL technique were used. RESULTS A significant decrease (p<0.01) in tissue zinc was observed and persisted after infection. Cytoarchitectural changes were observed in 75% of gerbils in the HGINV or WB groups. Ectopic pyramidal neurons were found in the cornus ammonis (CA1-CA3). At 60 and 90 days of age loss of lamination was clearly visible in CA1. In the dentate gyrus (DG), thinning of the dorsal lamina and abnormal thickening of the ventral lamina were observed from 30 days of age. In the cerebellum, we found an increase (p<0.01) in the thickness of the external granular layer (EGL) at 14 days of age that persisted until day 21 (C 3 ± 0.3 μm; HGINV 37 ± 5 μm; WB 28 ± 3 μm); Purkinje cell population estimation showed a significant decrease; a large number of apoptotic somas were observed scattered in the molecular layer; in 60 and 90 days old gerbils we found granular cell heterotopia and Purkinje cell ectopia. The pattern of apoptosis was different in the cerebellum and hippocampus of parasitized gerbils. CONCLUSION The morphological changes found suggest that neuronal migration is affected by zinc depletion caused by giardiasis in early postnatal life; for the first time, the link between giardiasis-zinc depletion and damaged brain structures is shown. This damage may explain the psychomotor/cognitive delay associated with giardiasis. These findings are alarming. Alterations in zinc metabolism and signalling are known to be involved in many brain disorders, including autism.
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Affiliation(s)
- Angélica González Maciel
- Laboratory of Cell and Tissue Morphology, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, Mexico
| | - Laura Elizabeth Rosas López
- Laboratory of Cell and Tissue Morphology, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, Mexico
| | - Rosa María Romero-Velázquez
- Laboratory of Cell and Tissue Morphology, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, Mexico
| | - Andrea Ramos-Morales
- Laboratory of Cell and Tissue Morphology, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, Mexico
| | - Martha Ponce-Macotela
- Laboratory of Experimental Parasitology, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, Mexico
| | - David Calderón-Guzmán
- Laboratory of Neuroscience, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, Mexico
| | | | - Alfonso Alfaro-Rodríguez
- Division of Neurosciences, Instituto Nacional de Rehabilitación, "Luis Guillermo Ibarra Ibarra", Secretaría de Salud, Mexico City, Mexico
| | - Rafael Reynoso-Robles
- Laboratory of Cell and Tissue Morphology, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, Mexico
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6
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Liu J, Zhang H. Zinc Finger and BTB Domain-Containing 20: A Newly Emerging Player in Pathogenesis and Development of Human Cancers. Biomolecules 2024; 14:192. [PMID: 38397429 PMCID: PMC10887282 DOI: 10.3390/biom14020192] [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: 01/12/2024] [Revised: 01/30/2024] [Accepted: 02/02/2024] [Indexed: 02/25/2024] Open
Abstract
Zinc finger and BTB domain-containing 20 (ZBTB20), which was initially identified in human dendritic cells, belongs to a family of transcription factors (TFs) with an N-terminal BTB domain and one or more C-terminal DNA-binding zinc finger domains. Under physiological conditions, ZBTB20 acts as a transcriptional repressor in cellular development and differentiation, metabolism, and innate immunity. Interestingly, multiple lines of evidence from mice and human systems have revealed the importance of ZBTB20 in the pathogenesis and development of cancers. ZBTB20 is not only a hotspot of genetic variation or fusion in many types of human cancers, but also a key TF or intermediator involving in the dysregulation of cancer cells. Given the diverse functions of ZBTB20 in both health and disease, we herein summarize the structure and physiological roles of ZBTB20, with an emphasis on the latest findings on tumorigenesis and cancer progression.
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Affiliation(s)
| | - Han Zhang
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650118, China;
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7
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Bilgic Eltan S, Nain E, Catak MC, Ezen E, Sefer AP, Karimi N, Kiykim A, Kolukisa B, Baser D, Bulutoglu A, Kasap N, Yorgun Altunbas M, Yalcin Gungoren E, Kendir Demirkol Y, Kutlug S, Hancioglu G, Dilek F, Yildiran A, Ozen A, Karakoc-Aydiner E, Erman B, Baris S. Evaluation of Clinical and Immunological Alterations Associated with ICF Syndrome. J Clin Immunol 2023; 44:26. [PMID: 38129713 DOI: 10.1007/s10875-023-01620-6] [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: 08/22/2023] [Accepted: 11/20/2023] [Indexed: 12/23/2023]
Abstract
PURPOSE Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a rare autosomal recessive combined immunodeficiency. The detailed immune responses are not explored widely. We investigated known and novel immune alterations in lymphocyte subpopulations and their association with clinical symptoms in a well-defined ICF cohort. METHODS We recruited the clinical findings from twelve ICF1 and ICF2 patients. We performed detailed immunological evaluation, including lymphocyte subset analyses, upregulation, and proliferation of T cells. We also determined the frequency of circulating T follicular helper (cTFH) and regulatory T (Treg) cells and their subtypes by flow cytometry. RESULTS There were ten ICF1 and two ICF2 patients. We identified two novel homozygous missense mutations in the ZBTB24 gene. Respiratory tract infections were the most common recurrent infections among the patients. Gastrointestinal system (GIS) involvements were observed in seven patients. All patients received intravenous immunoglobulin replacement therapy and antibacterial prophylaxis; two died during the follow-up period. Immunologically, CD4+ T-cell counts, percentages of recent thymic emigrant T cells, and naive CD4+ T decreased in two, five, and four patients, respectively. Impaired T-cell proliferation and reduced CD25 upregulation were detected in all patients. These changes were more prominent in CD8+ T cells. GIS involvements negatively correlated with CD3+ T-, CD3+CD4+ T-, CD16+CD56+ NK-cell counts, and CD4+/CD8+ T-cell ratios. Further, we observed expanded cTFH cells and reduced Treg and follicular regulatory T cells with a skewing to a TH2-like phenotype in all tested subpopulations. CONCLUSION The ICF syndrome encompasses various manifestations affecting multiple end organs. Perturbed T-cell responses with increased cTFH and decreased Treg cells may provide further insight into the immune aberrations observed in ICF syndrome.
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Affiliation(s)
- Sevgi Bilgic Eltan
- Pediatric Allergy and Immunology, Faculty of Medicine, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
| | - Ercan Nain
- Pediatric Allergy and Immunology, Faculty of Medicine, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
| | - Mehmet Cihangir Catak
- Pediatric Allergy and Immunology, Faculty of Medicine, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
| | - Ege Ezen
- Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Bogazici University, Istanbul, Turkey
| | - Asena Pınar Sefer
- Pediatric Allergy and Immunology, Faculty of Medicine, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
| | - Nastaran Karimi
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ayca Kiykim
- Pediatric Allergy and Immunology, Faculty of Medicine, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
| | - Burcu Kolukisa
- Pediatric Allergy and Immunology, Faculty of Medicine, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
| | - Dilek Baser
- Pediatric Allergy and Immunology, Faculty of Medicine, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
| | - Alper Bulutoglu
- Pediatric Allergy and Immunology, Faculty of Medicine, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
| | - Nurhan Kasap
- Pediatric Allergy and Immunology, Faculty of Medicine, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
| | - Melek Yorgun Altunbas
- Pediatric Allergy and Immunology, Faculty of Medicine, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
| | - Ezgi Yalcin Gungoren
- Pediatric Allergy and Immunology, Faculty of Medicine, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
| | - Yasemin Kendir Demirkol
- Division of Pediatric Genetics, Umraniye Education and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Seyhan Kutlug
- Division of Pediatric Immunology and Allergy, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey
| | - Gonca Hancioglu
- Division of Pediatric Immunology and Allergy, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey
| | - Fatih Dilek
- Department of Pediatrics, Faculty of Medicine, Atlas University, Istanbul, Turkey
| | - Alisan Yildiran
- Division of Pediatric Immunology and Allergy, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey
| | - Ahmet Ozen
- Pediatric Allergy and Immunology, Faculty of Medicine, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
| | - Elif Karakoc-Aydiner
- Pediatric Allergy and Immunology, Faculty of Medicine, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
| | - Batu Erman
- Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Bogazici University, Istanbul, Turkey
| | - Safa Baris
- Pediatric Allergy and Immunology, Faculty of Medicine, Marmara University, Istanbul, Turkey.
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey.
- The Isil Berat Barlan Center for Translational Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey.
- Pediatric Allergy and Immunology, Marmara University Hospital, Istanbul, Turkey.
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8
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Preiss NK, Kamal Y, Wilkins OM, Li C, Kolling FW, Trask HW, Usherwood YK, Cheng C, Frost HR, Usherwood EJ. Characterizing control of memory CD8 T cell differentiation by BTB-ZF transcription factor Zbtb20. Life Sci Alliance 2023; 6:e202201683. [PMID: 37414528 PMCID: PMC10326419 DOI: 10.26508/lsa.202201683] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 06/14/2023] [Accepted: 06/15/2023] [Indexed: 07/08/2023] Open
Abstract
Members of the BTB-ZF transcription factor family regulate the immune system. Our laboratory identified that family member Zbtb20 contributes to the differentiation, recall responses, and metabolism of CD8 T cells. Here, we report a characterization of the transcriptional and epigenetic signatures controlled by Zbtb20 at single-cell resolution during the effector and memory phases of the CD8 T cell response. Without Zbtb20, transcriptional programs associated with memory CD8 T cell formation were up-regulated throughout the CD8 T response. A signature of open chromatin was associated with genes controlling T cell activation, consistent with the known impact on differentiation. In addition, memory CD8 T cells lacking Zbtb20 were characterized by open chromatin regions with overrepresentation of AP-1 transcription factor motifs and elevated RNA- and protein-level expressions of the corresponding AP-1 components. Finally, we describe motifs and genomic annotations from the DNA targets of Zbtb20 in CD8 T cells identified by cleavage under targets and release under nuclease (CUT&RUN). Together, these data establish the transcriptional and epigenetic networks contributing to the control of CD8 T cell responses by Zbtb20.
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Affiliation(s)
- Nicholas K Preiss
- Microbiology and Immunology Department, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Yasmin Kamal
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Owen M Wilkins
- Department of Biomedical Data Science, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA
- Genomics and Molecular Biology Shared Resource, Dartmouth Cancer Center, Geisel School of Medicine, Lebanon, NH, USA
| | - Chenyang Li
- Genomic Medicine Department, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center UTHealth Houston, Houston, TX, USA
| | - Fred W Kolling
- Genomics and Molecular Biology Shared Resource, Dartmouth Cancer Center, Geisel School of Medicine, Lebanon, NH, USA
| | - Heidi W Trask
- Genomics and Molecular Biology Shared Resource, Dartmouth Cancer Center, Geisel School of Medicine, Lebanon, NH, USA
| | - Young-Kwang Usherwood
- Microbiology and Immunology Department, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Chao Cheng
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
- The Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA
| | - Hildreth R Frost
- Department of Biomedical Data Science, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA
| | - Edward J Usherwood
- Microbiology and Immunology Department, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
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Mihailova V, Stoyanova II, Tonchev AB. Glial Populations in the Human Brain Following Ischemic Injury. Biomedicines 2023; 11:2332. [PMID: 37760773 PMCID: PMC10525766 DOI: 10.3390/biomedicines11092332] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 08/14/2023] [Accepted: 08/19/2023] [Indexed: 09/29/2023] Open
Abstract
There is a growing interest in glial cells in the central nervous system due to their important role in maintaining brain homeostasis under physiological conditions and after injury. A significant amount of evidence has been accumulated regarding their capacity to exert either pro-inflammatory or anti-inflammatory effects under different pathological conditions. In combination with their proliferative potential, they contribute not only to the limitation of brain damage and tissue remodeling but also to neuronal repair and synaptic recovery. Moreover, reactive glial cells can modulate the processes of neurogenesis, neuronal differentiation, and migration of neurons in the existing neural circuits in the adult brain. By discovering precise signals within specific niches, the regulation of sequential processes in adult neurogenesis holds the potential to unlock strategies that can stimulate the generation of functional neurons, whether in response to injury or as a means of addressing degenerative neurological conditions. Cerebral ischemic stroke, a condition falling within the realm of acute vascular disorders affecting the circulation in the brain, stands as a prominent global cause of disability and mortality. Extensive investigations into glial plasticity and their intricate interactions with other cells in the central nervous system have predominantly relied on studies conducted on experimental animals, including rodents and primates. However, valuable insights have also been gleaned from in vivo studies involving poststroke patients, utilizing highly specialized imaging techniques. Following the attempts to map brain cells, the role of various transcription factors in modulating gene expression in response to cerebral ischemia is gaining increasing popularity. Although the results obtained thus far remain incomplete and occasionally ambiguous, they serve as a solid foundation for the development of strategies aimed at influencing the recovery process after ischemic brain injury.
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Affiliation(s)
- Victoria Mihailova
- Department of Anatomy and Cell Biology, Faculty of Medicine, Medical University Varna, 9000 Varna, Bulgaria; (I.I.S.); (A.B.T.)
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10
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Xie Z, Ma XH, Bai QF, Tang J, Sun JH, Jiang F, Guo W, Wang CM, Yang R, Wen YC, Wang FY, Chen YX, Zhang H, He DZ, Kelley MW, Yang S, Zhang WJ. ZBTB20 is essential for cochlear maturation and hearing in mice. Proc Natl Acad Sci U S A 2023; 120:e2220867120. [PMID: 37279265 PMCID: PMC10268240 DOI: 10.1073/pnas.2220867120] [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: 12/11/2022] [Accepted: 04/25/2023] [Indexed: 06/08/2023] Open
Abstract
The mammalian cochlear epithelium undergoes substantial remodeling and maturation before the onset of hearing. However, very little is known about the transcriptional network governing cochlear late-stage maturation and particularly the differentiation of its lateral nonsensory region. Here, we establish ZBTB20 as an essential transcription factor required for cochlear terminal differentiation and maturation and hearing. ZBTB20 is abundantly expressed in the developing and mature cochlear nonsensory epithelial cells, with transient expression in immature hair cells and spiral ganglion neurons. Otocyst-specific deletion of Zbtb20 causes profound deafness with reduced endolymph potential in mice. The subtypes of cochlear epithelial cells are normally generated, but their postnatal development is arrested in the absence of ZBTB20, as manifested by an immature appearance of the organ of Corti, malformation of tectorial membrane (TM), a flattened spiral prominence (SP), and a lack of identifiable Boettcher cells. Furthermore, these defects are related with a failure in the terminal differentiation of the nonsensory epithelium covering the outer border Claudius cells, outer sulcus root cells, and SP epithelial cells. Transcriptome analysis shows that ZBTB20 regulates genes encoding for TM proteins in the greater epithelial ridge, and those preferentially expressed in root cells and SP epithelium. Our results point to ZBTB20 as an essential regulator for postnatal cochlear maturation and particularly for the terminal differentiation of cochlear lateral nonsensory domain.
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Affiliation(s)
- Zhifang Xie
- Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Institute of Early Life Health, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai200092, China
- Department of Pathophysiology, Naval Medical University, Shanghai200433, China
| | - Xian-Hua Ma
- Department of Pathophysiology, Naval Medical University, Shanghai200433, China
| | - Qiu-Fang Bai
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin300134, China
| | - Jie Tang
- Department of Physiology, Southern Medical University, Guangzhou, Guangdong510515, China
| | - Jian-He Sun
- Senior Department of Otolaryngology-Head and Neck Surgery, National Clinical Research Center for Otolaryngologic Diseases, the Sixth Medical Center of PLA General Hospital, Beijing100141, China
| | - Fei Jiang
- Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Institute of Early Life Health, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai200092, China
| | - Wei Guo
- Senior Department of Otolaryngology-Head and Neck Surgery, National Clinical Research Center for Otolaryngologic Diseases, the Sixth Medical Center of PLA General Hospital, Beijing100141, China
| | - Chen-Ma Wang
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin300134, China
| | - Rui Yang
- Department of Pathophysiology, Naval Medical University, Shanghai200433, China
| | - Yin-Chuan Wen
- Department of Physiology, Southern Medical University, Guangzhou, Guangdong510515, China
| | - Fang-Yuan Wang
- Senior Department of Otolaryngology-Head and Neck Surgery, National Clinical Research Center for Otolaryngologic Diseases, the Sixth Medical Center of PLA General Hospital, Beijing100141, China
| | - Yu-Xia Chen
- Department of Pathophysiology, Naval Medical University, Shanghai200433, China
| | - Hai Zhang
- Department of Pathophysiology, Naval Medical University, Shanghai200433, China
| | - David Z. He
- Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE68178
| | | | - Shiming Yang
- Senior Department of Otolaryngology-Head and Neck Surgery, National Clinical Research Center for Otolaryngologic Diseases, the Sixth Medical Center of PLA General Hospital, Beijing100141, China
| | - Weiping J. Zhang
- Department of Pathophysiology, Naval Medical University, Shanghai200433, China
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin300134, China
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11
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Pan B, Han B, Zhu X, Wang Y, Ji H, Weng J, Liu Y. Dysfunctional microRNA-144-3p/ZBTB20/ERK/CREB1 signalling pathway is associated with MK-801-induced schizophrenia-like abnormalities. Brain Res 2022; 1798:148153. [DOI: 10.1016/j.brainres.2022.148153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/14/2022] [Accepted: 10/31/2022] [Indexed: 11/05/2022]
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12
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Dunville K, Tonelli F, Novelli E, Codino A, Massa V, Frontino AM, Galfrè S, Biondi F, Gustincich S, Caleo M, Pandolfini L, Alia C, Cremisi F. Laminin 511 and WNT signalling sustain prolonged expansion of hiPSC-derived hippocampal progenitors. Development 2022; 149:276383. [DOI: 10.1242/dev.200353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 08/08/2022] [Indexed: 11/20/2022]
Abstract
ABSTRACT
Using the timely re-activation of WNT signalling in neuralizing human induced pluripotent stem cells (hiPSCs), we have produced neural progenitor cells with a gene expression profile typical of human embryonic dentate gyrus (DG) cells. Notably, in addition to continuous WNT signalling, a specific laminin isoform is crucial to prolonging the neural stem state and to extending progenitor cell proliferation for over 200 days in vitro. Laminin 511 is indeed specifically required to support proliferation and to inhibit differentiation of hippocampal progenitor cells for extended time periods when compared with a number of different laminin isoforms assayed. Global gene expression profiles of these cells suggest that a niche of laminin 511 and WNT signalling is sufficient to maintain their capability to undergo typical hippocampal neurogenesis. Moreover, laminin 511 signalling sustains the expression of a set of genes responsible for the maintenance of a hippocampal neurogenic niche. Finally, xenograft of human DG progenitors into the DG of adult immunosuppressed host mice produces efficient integration of neurons that innervate CA3 layer cells spanning the same area of endogenous hippocampal neuron synapses.
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Affiliation(s)
- Keagan Dunville
- Laboratorio di Biologia, Scuola Normale Superiore 1 , Pisa, 56126 , Italy
| | - Fabrizio Tonelli
- Laboratorio di Biologia, Scuola Normale Superiore 1 , Pisa, 56126 , Italy
| | - Elena Novelli
- Istituto di Neuroscienze, Consiglio Nazionale delle Ricerche 2 , Pisa, 56124 , Italy
| | - Azzurra Codino
- Center for Human Technologies, Central RNA Lab, Istituto Italiano di Tecnologia 3 , Genova, 16152 , Italy
| | - Verediana Massa
- Istituto di Neuroscienze, Consiglio Nazionale delle Ricerche 2 , Pisa, 56124 , Italy
| | | | - Silvia Galfrè
- Department of Biology and Biotechnologies ‘Charles Darwin’, Università La Sapienza 4 , Roma, 00185 , Italy
| | - Francesca Biondi
- Istituto di Neuroscienze, Consiglio Nazionale delle Ricerche 2 , Pisa, 56124 , Italy
| | - Stefano Gustincich
- Center for Human Technologies, Central RNA Lab, Istituto Italiano di Tecnologia 3 , Genova, 16152 , Italy
| | - Matteo Caleo
- Istituto di Neuroscienze, Consiglio Nazionale delle Ricerche 2 , Pisa, 56124 , Italy
| | - Luca Pandolfini
- Center for Human Technologies, Central RNA Lab, Istituto Italiano di Tecnologia 3 , Genova, 16152 , Italy
| | - Claudia Alia
- Istituto di Neuroscienze, Consiglio Nazionale delle Ricerche 2 , Pisa, 56124 , Italy
| | - Federico Cremisi
- Laboratorio di Biologia, Scuola Normale Superiore 1 , Pisa, 56126 , Italy
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13
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Farrell C, Mumford P, Wiseman FK. Rodent Modeling of Alzheimer's Disease in Down Syndrome: In vivo and ex vivo Approaches. Front Neurosci 2022; 16:909669. [PMID: 35747206 PMCID: PMC9209729 DOI: 10.3389/fnins.2022.909669] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/16/2022] [Indexed: 12/30/2022] Open
Abstract
There are an estimated 6 million people with Down syndrome (DS) worldwide. In developed countries, the vast majority of these individuals will develop Alzheimer's disease neuropathology characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles within the brain, which leads to the early onset of dementia (AD-DS) and reduced life-expectancy. The mean age of onset of clinical dementia is ~55 years and by the age of 80, approaching 100% of individuals with DS will have a dementia diagnosis. DS is caused by trisomy of chromosome 21 (Hsa21) thus an additional copy of a gene(s) on the chromosome must cause the development of AD neuropathology and dementia. Indeed, triplication of the gene APP which encodes the amyloid precursor protein is sufficient and necessary for early onset AD (EOAD), both in people who have and do not have DS. However, triplication of other genes on Hsa21 leads to profound differences in neurodevelopment resulting in intellectual disability, elevated incidence of epilepsy and perturbations to the immune system. This different biology may impact on how AD neuropathology and dementia develops in people who have DS. Indeed, genes on Hsa21 other than APP when in three-copies can modulate AD-pathogenesis in mouse preclinical models. Understanding this biology better is critical to inform drug selection for AD prevention and therapy trials for people who have DS. Here we will review rodent preclinical models of AD-DS and how these can be used for both in vivo and ex vivo (cultured cells and organotypic slice cultures) studies to understand the mechanisms that contribute to the early development of AD in people who have DS and test the utility of treatments to prevent or delay the development of disease.
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14
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Medeiros de Araújo JA, Barão S, Mateos-White I, Espinosa A, Costa MR, Gil-Sanz C, Müller U. ZBTB20 is crucial for the specification of a subset of callosal projection neurons and astrocytes in the mammalian neocortex. Development 2021; 148:271200. [PMID: 34351428 DOI: 10.1242/dev.196642] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 07/17/2021] [Indexed: 12/25/2022]
Abstract
Neocortical progenitor cells generate subtypes of excitatory projection neurons in sequential order followed by the generation of astrocytes. The transcription factor zinc finger and BTB domain-containing protein 20 (ZBTB20) has been implicated in regulation of cell specification during neocortical development. Here, we show that ZBTB20 instructs the generation of a subset of callosal projections neurons in cortical layers II/III in mouse. Conditional deletion of Zbtb20 in cortical progenitors, and to a lesser degree in differentiating neurons, leads to an increase in the number of layer IV neurons at the expense of layer II/III neurons. Astrogliogenesis is also affected in the mutants with an increase in the number of a specific subset of astrocytes expressing GFAP. Astrogliogenesis is more severely disrupted by a ZBTB20 protein containing dominant mutations linked to Primrose syndrome, suggesting that ZBTB20 acts in concert with other ZBTB proteins that were also affected by the dominant-negative protein to instruct astrogliogenesis. Overall, our data suggest that ZBTB20 acts both in progenitors and in postmitotic cells to regulate cell fate specification in the mammalian neocortex.
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Affiliation(s)
- Jéssica Alves Medeiros de Araújo
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Brain Institute, Federal University of Rio Grande do Norte, Natal, RN 59056-450, Brazil
| | - Soraia Barão
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Isabel Mateos-White
- BIOTECMED Institute, Universidad de Valencia, Burjassot, Valencia 46100, Spain
| | - Ana Espinosa
- AntalGenics, Quorum Building III, Scientific Park - UMH. Avda. de la Universidad, s/n. 03202 Elche (Alicante), Spain
| | - Marcos Romualdo Costa
- Brain Institute, Federal University of Rio Grande do Norte, Natal, RN 59056-450, Brazil.,Unité INSERM 1167, RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, Institut Pasteur de Lille, University of Lille, U1167-Excellence Laboratory LabEx DISTALZ, Lille Cedex 59019, France
| | - Cristina Gil-Sanz
- BIOTECMED Institute, Universidad de Valencia, Burjassot, Valencia 46100, Spain
| | - Ulrich Müller
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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15
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den Hoed J, Devaraju K, Fisher SE. Molecular networks of the FOXP2 transcription factor in the brain. EMBO Rep 2021; 22:e52803. [PMID: 34260143 PMCID: PMC8339667 DOI: 10.15252/embr.202152803] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 05/19/2021] [Accepted: 06/23/2021] [Indexed: 01/06/2023] Open
Abstract
The discovery of the FOXP2 transcription factor, and its implication in a rare severe human speech and language disorder, has led to two decades of empirical studies focused on uncovering its roles in the brain using a range of in vitro and in vivo methods. Here, we discuss what we have learned about the regulation of FOXP2, its downstream effectors, and its modes of action as a transcription factor in brain development and function, providing an integrated overview of what is currently known about the critical molecular networks.
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Affiliation(s)
- Joery den Hoed
- Language and Genetics DepartmentMax Planck Institute for PsycholinguisticsNijmegenThe Netherlands
- International Max Planck Research School for Language SciencesMax Planck Institute for PsycholinguisticsNijmegenThe Netherlands
| | - Karthikeyan Devaraju
- Language and Genetics DepartmentMax Planck Institute for PsycholinguisticsNijmegenThe Netherlands
| | - Simon E Fisher
- Language and Genetics DepartmentMax Planck Institute for PsycholinguisticsNijmegenThe Netherlands
- Donders Institute for Brain, Cognition and BehaviourRadboud UniversityNijmegenThe Netherlands
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16
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An association study in the Taiwan Biobank elicits three novel candidates for cognitive aging in old adults: NCAM1, TTC12 and ZBTB20. Aging (Albany NY) 2021; 13:18769-18788. [PMID: 34285142 PMCID: PMC8351692 DOI: 10.18632/aging.203321] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 07/08/2021] [Indexed: 01/11/2023]
Abstract
The dopamine receptor-related loci have been suggested to be associated with cognitive functions and neurodegenerative diseases. It is unknown whether genetic variants such as single nucleotide polymorphisms (SNPs) in the dopamine receptor-related loci could contribute to cognitive aging independently as well as by virtue of complicated interplays in the elder population. To assess whether SNPs in the dopamine receptor-related loci are associated with cognitive aging in the elder population, we evaluated SNPs in the DRD1, NCAM1-TTC12-ANKK1-DRD2, DRD3-LOC107986115-ZNF80-TIGIT-MIR568-ZBTB20, DRD4, and DRD5-SLC2A9 loci from 25,195 older Taiwanese individuals from the Taiwan Biobank. Mini-Mental State Examination (MMSE) was scrutinized for all participants, where MMSE scores were employed to evaluate cognitive functions. From our analysis, we identified three novel genes for cognitive aging that have not previously been reported: ZBTB20 on chromosome 3 and NCAM1 and TTC12 on chromosome 11. NCAM1 and ZBTB20 are strong candidates for having a role in cognitive aging with mutations in ZBTB20 resulting in intellectual disability, and NCAM1 previously found to be associated with associative memory in humans. Additionally, we found the effects of interplays between physical activity and these three novel genes. Our study suggests that genetic variants in the dopamine receptor-related loci may influence cognitive aging individually and by means of gene-physical activity interactions.
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17
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Phenotypic Differences between the Alzheimer's Disease-Related hAPP-J20 Model and Heterozygous Zbtb20 Knock-Out Mice. eNeuro 2021; 8:ENEURO.0089-21.2021. [PMID: 33833046 PMCID: PMC8121260 DOI: 10.1523/eneuro.0089-21.2021] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 03/30/2021] [Accepted: 04/02/2021] [Indexed: 12/20/2022] Open
Abstract
Diverse gene products contribute to the pathogenesis of Alzheimer’s disease (AD). Experimental models have helped elucidate their mechanisms and impact on brain functions. Human amyloid precursor protein (hAPP) transgenic mice from line J20 (hAPP-J20 mice) are widely used to simulate key aspects of AD. However, they also carry an insertional mutation in noncoding sequence of one Zbtb20 allele, a gene involved in neural development. We demonstrate that heterozygous hAPP-J20 mice have reduced Zbtb20 expression in some AD-relevant brain regions, but not others, and that Zbtb20 levels are higher in hAPP-J20 mice than heterozygous Zbtb20 knock-out (Zbtb20+/–) mice. Whereas hAPP-J20 mice have premature mortality, severe deficits in learning and memory, other behavioral alterations, and prominent nonconvulsive epileptiform activity, Zbtb20+/– mice do not. Thus, the insertional mutation in hAPP-J20 mice does not ablate the affected Zbtb20 allele and is unlikely to account for the AD-like phenotype of this model.
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18
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To JC, Chiu AP, Tschida BR, Lo LH, Chiu CH, Li XX, Kuka TP, Linden MA, Amin K, Chan WC, Bell JB, Moriarity BS, Largaespada DA, Keng VW. ZBTB20 regulates WNT/CTNNB1 signalling pathway by suppressing PPARG during hepatocellular carcinoma tumourigenesis. JHEP Rep 2020; 3:100223. [PMID: 33604532 PMCID: PMC7873381 DOI: 10.1016/j.jhepr.2020.100223] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 11/17/2020] [Accepted: 12/03/2020] [Indexed: 01/19/2023] Open
Abstract
Background & Aims Zinc finger and BTB domain containing 20 (ZBTB20) has been implicated as a potential oncogene in liver cancer. However, knockout studies have shown it to be a transcriptional repressor of the alpha-foetoprotein (Afp) gene in adult liver, and reduced levels of ZBTB20 allow for upregulation of AFP with increased tumour severity in certain cases of hepatocellular carcinoma (HCC). As there are many discrepancies in the literature regarding its role in liver tumourigenesis, the aim of this study was to elucidate the role of ZBTB20 in HCC tumourigenesis. Methods A reverse genetic study using the Sleeping Beauty (SB) transposon system in mice was performed to elucidate the role of ZBTB20 in HCC tumourigenesis. In vitro ZBTB20 gain- and loss-of-function experiments were used to assess the relationship amongst ZBTB20, peroxisome proliferator activated receptor gamma (PPARG) and catenin beta 1 (CTNNB1). Results Transgenic overexpression of ZBTB20 in hepatocytes and in the context of transformation related protein (T r p53) inactivation induced hepatic hypertrophy, activation of WNT/CTNNB1 signalling, and development of liver tumours. In vitro overexpression and knockout experiments using CRISPR/Cas9 demonstrated the important role for ZBTB20 in downregulating PPARG, resulting in activation of the WNT/CTNNB1 signalling pathway and its downstream effectors in HCC tumourigenesis. Conclusions These findings demonstrate a novel interaction between ZBTB20 and PPARG, which leads to activation of the WNT/CTNNB1 signalling pathway in HCC tumourigenesis. Lay summary ZBTB20 has been implicated as a potential oncogene in liver cancer. Herein, we uncover its important role in liver cancer development. We show that it interacts with PPARG to upregulate the WNT/CTNNB1 signalling pathway, leading to tumourigenesis.
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Key Words
- AFP, alpha-foetoprotein
- BTB/POZ, broad complex
- CTNNB1
- CTNNB1, catenin beta 1
- Fah, fumarylacetoacetate hydrolase
- GSK3B, glycogen synthase kinase 3 beta
- HCC, hepatocellular carcinoma
- HHL, immortalized human hepatic cell line
- Hepatocellular carcinoma
- IF, immunofluorescence
- NTBC, 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione
- OFP, orange fluorescent protein
- PHI, post-hydrodynamic injection
- POK, POZ and Kruppel
- PPARG
- PPARG, peroxisome proliferator activated receptor gamma
- Reverse genetic screen
- SB, Sleeping Beauty
- Sleeping Beauty
- ZBTB20
- ZBTB20, zinc finger and BTB domain containing 20
- qPCR, quantitative RT-PCR
- tramtrack, bric a brac/poxvirus and zinc finger
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Affiliation(s)
- Jeffrey C To
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR
| | - Amy P Chiu
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR
| | - Barbara R Tschida
- Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Lilian H Lo
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR
| | - Cynthia H Chiu
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR
| | - Xiao-Xiao Li
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR
| | - Timothy P Kuka
- Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, MN, 55455, USA.,College of Natural Sciences, The University of Texas at Austin, Austin, TX, 78712, USA
| | - Michael A Linden
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Khalid Amin
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Wing-Cheung Chan
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR
| | - Jason B Bell
- Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Branden S Moriarity
- Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, MN, 55455, USA
| | - David A Largaespada
- Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Vincent W Keng
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR.,State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR
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19
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Ren AJ, Chen C, Zhang S, Liu M, Wei C, Wang K, Ma X, Song Y, Wang R, Zhang H, Chen YX, Wu H, Xie Z, Zhang Y, Zhang WJ. Zbtb20 deficiency causes cardiac contractile dysfunction in mice. FASEB J 2020; 34:13862-13876. [PMID: 32844471 DOI: 10.1096/fj.202000160rr] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 08/04/2020] [Accepted: 08/07/2020] [Indexed: 12/15/2022]
Abstract
The zinc-finger protein ZBTB20 regulates development and metabolism in multiple systems, and is essential for postnatal survival in mice. However, its potential role in the cardiovascular system remains undefined. Here, we demonstrate that ZBTB20 is critically involved in the regulation of cardiac contractility and blood pressure in mice. At the age of 16 days, the relatively healthy Zbtb20-null mice exhibited hypotension without obvious change of heart rate or other evidence for heart failure. Moreover, Zbtb20 deletion led to a marked reduction in heart size, left ventricular wall thickness, and cell size of cardiomyocytes, which was largely proportional to the decreased body growth. Notably, echocardiographic and hemodynamic analyses showed that cardiac contractility was greatly impaired in the absence of ZBTB20. Mechanistically, ZBTB20 deficiency decreased cardiac ATP contents, and compromised the enzyme activity of mitochondrial complex I in heart as well as L-type calcium current density in cardiomyocytes. Furthermore, the developmental activation of some mitochondrial function-related genes was significantly attenuated in Zbtb20-null myocardium, which included Hspb8, Ckmt2, Cox7a1, Tfrc, and Ogdhl. Put together, these results suggest that ZBTB20 plays a crucial role in the regulation of heart development, energy metabolism, and contractility.
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Affiliation(s)
- An-Jing Ren
- Department of Pathophysiology, Naval Medical University, Shanghai, China
| | - Chao Chen
- Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China
| | - Sha Zhang
- Department of Pathophysiology, Naval Medical University, Shanghai, China.,Department of Cardiovascular Diseases, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Mengna Liu
- Department of Pathophysiology, Naval Medical University, Shanghai, China
| | - Chunchun Wei
- Department of Pathophysiology, Naval Medical University, Shanghai, China
| | - Kai Wang
- Department of Pathophysiology, Naval Medical University, Shanghai, China
| | - Xianhua Ma
- Department of Pathophysiology, Naval Medical University, Shanghai, China
| | - Yao Song
- Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China
| | - Rui Wang
- Department of Pathophysiology, Naval Medical University, Shanghai, China
| | - Hai Zhang
- Department of Pathophysiology, Naval Medical University, Shanghai, China
| | - Yu-Xia Chen
- Department of Pathophysiology, Naval Medical University, Shanghai, China
| | - Hong Wu
- Department of Cardiovascular Diseases, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zhifang Xie
- Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Youyi Zhang
- Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China
| | - Weiping J Zhang
- Department of Pathophysiology, Naval Medical University, Shanghai, China.,NHC Key Laboratory of Hormones and Development, Tianjin Institute of Endocrinology, Tianjin Medical University Chu Hsien-I Memorial Hospital, Tianjin, China
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20
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Melis D, Carvalho D, Barbaro-Dieber T, Espay AJ, Gambello MJ, Gener B, Gerkes E, Hitzert MM, Hove HB, Jansen S, Jira PE, Lachlan K, Menke LA, Narayanan V, Ortiz D, Overwater E, Posmyk R, Ramsey K, Rossi A, Sandoval RL, Stumpel C, Stuurman KE, Cordeddu V, Turnpenny P, Strisciuglio P, Tartaglia M, Unger S, Waters T, Turnbull C, Hennekam RC. Primrose syndrome: Characterization of the phenotype in 42 patients. Clin Genet 2020; 97:890-901. [PMID: 32266967 PMCID: PMC7384157 DOI: 10.1111/cge.13749] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 03/20/2020] [Accepted: 03/24/2020] [Indexed: 12/13/2022]
Abstract
Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down‐slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha‐fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype‐phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.
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Affiliation(s)
- Daniela Melis
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", Salerno, Italy.,Department of Translational Medical Science, Federico II University, Naples, Italy
| | - Daniel Carvalho
- Medical Genetic Unit, SARAH Network of Rehabilitation Hospitals, Brasilia, Brazil
| | | | - Alberto J Espay
- Department of Neurology, University of Cincinnati, Gardner Family Center for Parkinson's Disease and Movement Disorders, Cincinnati, Ohio, USA
| | - Michael J Gambello
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Blanca Gener
- Department of Genetics, BioCruces Bizkaia Health Research Institute, Hospital Universitario Cruces, Bizkaia, Spain
| | - Erica Gerkes
- Department of Genetics, University of Groningen, UMC Groningen, Groningen, The Netherlands
| | - Marrit M Hitzert
- Department of Genetics, University of Groningen, UMC Groningen, Groningen, The Netherlands
| | - Hanne B Hove
- Department of Pediatrics, Division of Rare Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Sandra Jansen
- Department of Human Genetics, Radboud UMC, Nijmegen, The Netherlands
| | - Petr E Jira
- Department of Pediatrics, Jeroen Bosch Hospital, 's-Hertogenbosch, The Netherlands
| | - Katherine Lachlan
- Wessex Clinical Genetics Service, University Hospitals of Southampton NHS Trust, Southampton, UK
| | - Leonie A Menke
- Department of Pediatrics, Amsterdam UMC, Amsterdam, The Netherlands
| | - Vinodh Narayanan
- Translational Genomic Research Institute, Center for Rare Childhood Disorders, Phoenix, Arizona, USA
| | - Damara Ortiz
- Medical Genetics Department, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pensylvania, USA
| | - Eline Overwater
- Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Renata Posmyk
- Department of Clinical Genetics, Podlaskie Medical Center, Bialystok, Poland
| | - Keri Ramsey
- Translational Genomic Research Institute, Center for Rare Childhood Disorders, Phoenix, Arizona, USA
| | - Alessandro Rossi
- Department of Translational Medical Science, Federico II University, Naples, Italy
| | | | - Constance Stumpel
- Department of Clinical Genetics and GROW School for Oncology and Developmental Biology, Maastricht UMC, Maastricht, The Netherlands
| | - Kyra E Stuurman
- Department of Clinical Genetics Erasmus Medical Center, Rotterdam, The Netherlands
| | - Viviana Cordeddu
- Department of Hematology, Oncology and Molecular Medicine, National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy
| | - Peter Turnpenny
- Clinical Genetics Department, Royal Devon & Exeter Healthcare NHS, Exeter, UK
| | - Pietro Strisciuglio
- Department of Translational Medical Science, Federico II University, Naples, Italy
| | - Marco Tartaglia
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy
| | - Sheela Unger
- Division of Genetic Medicine, University of Lausanne, Lausanne, Switzerland
| | - Todd Waters
- North Florida Regional Medical Center, Gainesville, Florida, USA
| | - Clare Turnbull
- Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
| | - Raoul C Hennekam
- Department of Pediatrics, Amsterdam UMC, Amsterdam, The Netherlands
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21
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Ripamonti S, Shomroni O, Rhee JS, Chowdhury K, Jahn O, Hellmann KP, Bonn S, Brose N, Tirard M. SUMOylation controls the neurodevelopmental function of the transcription factor Zbtb20. J Neurochem 2020; 154:647-661. [PMID: 32233089 DOI: 10.1111/jnc.15008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 02/12/2020] [Accepted: 03/10/2020] [Indexed: 12/15/2022]
Abstract
SUMOylation is a dynamic post-translational protein modification that primarily takes place in cell nuclei, where it plays a key role in multiple DNA-related processes. In neurons, the SUMOylation-dependent control of a subset of neuronal transcription factors is known to regulate various aspects of nerve cell differentiation, development, and function. In an unbiased screen for endogenous SUMOylation targets in the developing mouse brain, based on a His6 -HA-SUMO1 knock-in mouse line, we previously identified the transcription factor Zinc finger and BTB domain-containing 20 (Zbtb20) as a new SUMO1-conjugate. We show here that the three key SUMO paralogues SUMO1, SUMO2, and SUMO3 can all be conjugated to Zbtb20 in vitro in HEK293FT cells, and we confirm the SUMOylation of Zbtb20 in vivo in mouse brain. Using primary hippocampal neurons from wild-type and Zbtb20 knock-out (KO) mice as a model system, we then demonstrate that the expression of Zbtb20 is required for proper nerve cell development and neurite growth and branching. Furthermore, we show that the SUMOylation of Zbtb20 is essential for its function in this context, and provide evidence indicating that SUMOylation affects the Zbtb20-dependent transcriptional profile of neurons. Our data highlight the role of SUMOylation in the regulation of neuronal transcription factors that determine nerve cell development, and they demonstrate that key functions of the transcription factor Zbtb20 in neuronal development and neurite growth are under obligatory SUMOylation control.
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Affiliation(s)
- Silvia Ripamonti
- Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany
| | - Orr Shomroni
- NGS Integrative Genomics Core Unit, Department of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
| | - Jeong Seop Rhee
- Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany
| | - Kamal Chowdhury
- Max Planck Institute of Biophysical Chemistry, Göttingen, Germany
| | - Olaf Jahn
- Proteomics Group, Max Planck Institute of Experimental Medicine, Göttingen, Germany
| | - Klaus Peter Hellmann
- Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany
| | - Stefan Bonn
- Institute of Medical Systems Biology, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,German Center for Neurodegenerative Diseases, Tübingen, Germany
| | - Nils Brose
- Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany
| | - Marilyn Tirard
- Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany
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22
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Hemming IA, Clément O, Gladwyn-Ng IE, Cullen HD, Ng HL, See HB, Ngo L, Ulgiati D, Pfleger KDG, Agostino M, Heng JIT. Disease-associated missense variants in ZBTB18 disrupt DNA binding and impair the development of neurons within the embryonic cerebral cortex. Hum Mutat 2019; 40:1841-1855. [PMID: 31112317 DOI: 10.1002/humu.23803] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 05/08/2019] [Accepted: 05/19/2019] [Indexed: 12/12/2022]
Abstract
The activities of DNA-binding transcription factors, such as the multi-zinc-finger protein ZBTB18 (also known as RP58, or ZNF238), are essential to coordinate mammalian neurodevelopment, including the birth and radial migration of newborn neurons within the fetal brain. In humans, the majority of disease-associated missense mutations in ZBTB18 lie within the DNA-binding zinc-finger domain and are associated with brain developmental disorder, yet the molecular mechanisms explaining their role in disease remain unclear. To address this, we developed in silico models of ZBTB18, bound to DNA, and discovered that half of the missense variants map to residues (Asn461, Arg464, Glu486) predicted to be essential to sequence-specific DNA contact, whereas others map to residues (Leu434, Tyr447, Arg495) with limited contributions to DNA binding. We studied pathogenic variants to residues with close (N461S) and limited (R495G) DNA contact and found that each bound DNA promiscuously, displayed altered transcriptional regulatory activity in vitro, and influenced the radial migration of newborn neurons in vivo in different ways. Taken together, our results suggest that altered transcriptional regulation could represent an important pathological mechanism for ZBTB18 missense variants in brain developmental disease.
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Affiliation(s)
- Isabel A Hemming
- Molecular Medicine Division, QEII Medical Centre, The Harry Perkins Institute of Medical Research, Nedlands, Australia.,Centre for Medical Research, The University of Western Australia, Crawley, Australia.,Faculty of Health and Medical Sciences, Medical School, The University of Western Australia, Crawley, Australia
| | - Olivier Clément
- Molecular Medicine Division, QEII Medical Centre, The Harry Perkins Institute of Medical Research, Nedlands, Australia.,Centre for Medical Research, The University of Western Australia, Crawley, Australia.,Faculty of Health and Medical Sciences, Medical School, The University of Western Australia, Crawley, Australia.,School of Biomedical Sciences, Faculty of Health and Medical Sciences, The University of Western Australia, Crawley, Australia
| | - Ivan E Gladwyn-Ng
- Molecular Medicine Division, QEII Medical Centre, The Harry Perkins Institute of Medical Research, Nedlands, Australia.,Centre for Medical Research, The University of Western Australia, Crawley, Australia
| | - Hayley D Cullen
- Molecular Medicine Division, QEII Medical Centre, The Harry Perkins Institute of Medical Research, Nedlands, Australia.,Centre for Medical Research, The University of Western Australia, Crawley, Australia.,Faculty of Health and Medical Sciences, Medical School, The University of Western Australia, Crawley, Australia.,Curtin Health Innovation Research Institute, Curtin University, Bentley, Australia
| | - Han Leng Ng
- School of Biomedical Sciences, Faculty of Health and Medical Sciences, The University of Western Australia, Crawley, Australia
| | - Heng B See
- Molecular Medicine Division, QEII Medical Centre, The Harry Perkins Institute of Medical Research, Nedlands, Australia.,Centre for Medical Research, The University of Western Australia, Crawley, Australia
| | - Linh Ngo
- Molecular Medicine Division, QEII Medical Centre, The Harry Perkins Institute of Medical Research, Nedlands, Australia.,Centre for Medical Research, The University of Western Australia, Crawley, Australia
| | - Daniela Ulgiati
- School of Biomedical Sciences, Faculty of Health and Medical Sciences, The University of Western Australia, Crawley, Australia
| | - Kevin D G Pfleger
- Molecular Medicine Division, QEII Medical Centre, The Harry Perkins Institute of Medical Research, Nedlands, Australia.,Centre for Medical Research, The University of Western Australia, Crawley, Australia.,ARC Centre for Personalised Therapeutics Technologies, Melbourne, Australia
| | - Mark Agostino
- Curtin Health Innovation Research Institute, Curtin University, Bentley, Australia.,School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Australia.,Curtin Institute for Computation, Curtin University, Bentley, Australia
| | - Julian I-T Heng
- Curtin Health Innovation Research Institute, Curtin University, Bentley, Australia.,ARC Centre for Personalised Therapeutics Technologies, Melbourne, Australia.,School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Australia
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23
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Alby C, Boutaud L, Bessières B, Serre V, Rio M, Cormier-Daire V, de Oliveira J, Ichkou A, Mouthon L, Gordon CT, Bonnière M, Mechler C, Nitschke P, Bole C, Lyonnet S, Bahi-Buisson N, Boddaert N, Colleaux L, Roth P, Ville Y, Vekemans M, Encha-Razavi F, Attié-Bitach T, Thomas S. Novel de novo ZBTB20 mutations in three cases with Primrose syndrome and constant corpus callosum anomalies. Am J Med Genet A 2019; 176:1091-1098. [PMID: 29681083 DOI: 10.1002/ajmg.a.38684] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 02/16/2018] [Accepted: 02/25/2018] [Indexed: 11/06/2022]
Abstract
Corpus callosum (CC) is the major brain commissure connecting homologous areas of cerebral hemispheres. CC anomalies (CCAs) are the most frequent brain anomalies leading to variable neurodevelopmental outcomes making genetic counseling difficult in the absence of a known etiology that might inform the prognosis. Here, we used whole exome sequencing, and a targeted capture panel of syndromic CCA known causal and candidate genes to screen a cohort of 64 fetuses with CCA observed upon autopsy, and 34 children with CCA and intellectual disability. In one fetus and two patients, we identified three novel de novo mutations in ZBTB20, which was previously shown to be causal in Primrose syndrome. In addition to CCA, all cases presented with additional features of Primrose syndrome including facial dysmorphism and macrocephaly or megalencephaly. All three variations occurred within two out of the five zinc finger domains of the transcriptional repressor ZBTB20. Through homology modeling, these variants are predicted to result in local destabilization of each zinc finger domain suggesting subsequent abnormal repression of ZBTB20 target genes. Neurohistopathological analysis of the fetal case showed abnormal regionalization of the hippocampal formation as well as a reduced density of cortical upper layers where originate most callosal projections. Here, we report novel de novo ZBTB20 mutations in three independent cases with characteristic features of Primrose syndrome including constant CCA. Neurohistopathological findings in fetal case corroborate the observed key role of ZBTB20 during hippocampal and neocortical development. Finally, this study highlights the crucial role of ZBTB20 in CC development in human.
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Affiliation(s)
- Caroline Alby
- Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR1163 Institut Imagine, Paris, France.,Paris Descartes Sorbonne Paris Cité, Paris, France.,Department of genetics, Hospital Necker-Enfants Malades Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France
| | - Lucile Boutaud
- Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR1163 Institut Imagine, Paris, France.,Paris Descartes Sorbonne Paris Cité, Paris, France.,Department of genetics, Hospital Necker-Enfants Malades Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France
| | - Bettina Bessières
- Department of genetics, Hospital Necker-Enfants Malades Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France
| | - Valérie Serre
- UMR7592 CNRS Jacques Monod Institute Paris Diderot University, Paris, France
| | - Marlene Rio
- Department of genetics, Hospital Necker-Enfants Malades Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France
| | - Valerie Cormier-Daire
- Paris Descartes Sorbonne Paris Cité, Paris, France.,Department of genetics, Hospital Necker-Enfants Malades Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France.,Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR1163 Institut Imagine, Paris, France
| | - Judith de Oliveira
- Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR1163 Institut Imagine, Paris, France.,Department of genetics, Hospital Necker-Enfants Malades Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France
| | - Amale Ichkou
- Department of genetics, Hospital Necker-Enfants Malades Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France
| | - Linda Mouthon
- Department of genetics, Hospital Necker-Enfants Malades Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France
| | - Christopher T Gordon
- Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR1163 Institut Imagine, Paris, France.,Paris Descartes Sorbonne Paris Cité, Paris, France.,Department of genetics, Hospital Necker-Enfants Malades Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France
| | - Maryse Bonnière
- Department of genetics, Hospital Necker-Enfants Malades Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France
| | - Charlotte Mechler
- Department of genetics, Hospital Necker-Enfants Malades Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France
| | - Patrick Nitschke
- Paris Descartes Sorbonne Paris Cité, Paris, France.,Bioinformatics Core Facility Paris-Descartes Sorbonne Paris Cité University Institut Imagine, Paris, France
| | - Christine Bole
- Paris Descartes Sorbonne Paris Cité, Paris, France.,Genomics Core Facility, Paris Descartes-Sorbonne Paris Cité University Institut Imagine, Paris, France
| | - Stanislas Lyonnet
- Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR1163 Institut Imagine, Paris, France.,Paris Descartes Sorbonne Paris Cité, Paris, France.,Department of genetics, Hospital Necker-Enfants Malades Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France
| | - Nadia Bahi-Buisson
- Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR1163 Institut Imagine, Paris, France.,Paris Descartes Sorbonne Paris Cité, Paris, France.,Department of genetics, Hospital Necker-Enfants Malades Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France
| | - Nathalie Boddaert
- Paris Descartes Sorbonne Paris Cité, Paris, France.,Department of genetics, Hospital Necker-Enfants Malades Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France.,Department of Pediatric Radiology, Hospital Necker-Enfants Malades AP-HP, Paris, France
| | - Laurence Colleaux
- Paris Descartes Sorbonne Paris Cité, Paris, France.,Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, INSERM UMR1163 Institut Imagine, Paris, France
| | - Philippe Roth
- Department of Obstetrics and Fetal Medicine, Hospital Necker-Enfants-Malade APHP, Paris, France
| | - Yves Ville
- Department of Obstetrics and Fetal Medicine, Hospital Necker-Enfants-Malade APHP, Paris, France
| | - Michel Vekemans
- Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR1163 Institut Imagine, Paris, France.,Paris Descartes Sorbonne Paris Cité, Paris, France.,Department of genetics, Hospital Necker-Enfants Malades Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France
| | - Féréchté Encha-Razavi
- Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR1163 Institut Imagine, Paris, France.,Paris Descartes Sorbonne Paris Cité, Paris, France.,Department of genetics, Hospital Necker-Enfants Malades Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France
| | - Tania Attié-Bitach
- Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR1163 Institut Imagine, Paris, France.,Paris Descartes Sorbonne Paris Cité, Paris, France.,Department of genetics, Hospital Necker-Enfants Malades Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France
| | - Sophie Thomas
- Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR1163 Institut Imagine, Paris, France.,Paris Descartes Sorbonne Paris Cité, Paris, France
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24
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What do DNA methylation studies tell us about depression? A systematic review. Transl Psychiatry 2019; 9:68. [PMID: 30718449 PMCID: PMC6362194 DOI: 10.1038/s41398-019-0412-y] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 01/16/2019] [Accepted: 01/19/2019] [Indexed: 11/09/2022] Open
Abstract
There has been a limited number of systematic reviews conducted to summarize the overview of the relationship between DNA methylation and depression, and to critically appraise the roles of major study characteristics in the accuracy of study findings. This systematic review aims to critically appraise the impact of study characteristics on the association between DNA methylation and depression, and summarize the overview of this association. Electronic databases and gray literatures until December 2017 were searched for English-language studies with standard diagnostic criteria of depression. A total of 67 studies were included in this review along with a summary of their study characteristics. We grouped the findings into etiological and treatment studies. Majority of these selected studies were recently published and from developed countries. Whole blood samples were the most studied common tissues. Bisulfite conversion, along with pyrosequencing, was widely used to test the DNA methylation level across all the studies. High heterogeneity existed among the studies in terms of experimental and statistical methodologies and study designs. As recommended by the Cochrane guideline, a systematic review without meta-analysis should be undertaken. This review has, in general, found that DNA methylation modifications were associated with depression. Subgroup analyses showed that most studies found BDNF and SLC6A4 hypermethylations to be associated with MDD or depression in general. In contrast, studies on NR3C1, OXTR, and other genes, which were tested by only few studies, reported mixed findings. More longitudinal studies using standardized experimental and laboratory methodologies are needed in future studies to enable more systematical comparisons and quantitative synthesis.
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25
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Jones KA, Luo Y, Dukes-Rimsky L, Srivastava DP, Koul-Tewari R, Russell TA, Shapiro LP, Srivastava AK, Penzes P. Neurodevelopmental disorder-associated ZBTB20 gene variants affect dendritic and synaptic structure. PLoS One 2018; 13:e0203760. [PMID: 30281617 PMCID: PMC6169859 DOI: 10.1371/journal.pone.0203760] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 08/27/2018] [Indexed: 11/18/2022] Open
Abstract
Dendritic spine morphology and dendritic arborization are key determinants of neuronal connectivity and play critical roles in learning, memory and behavior function. Recently, defects of ZBTB20, a BTB and zinc finger domain containing transcriptional repressor, have been implicated in a wide range of neurodevelopmental disorders, including intellectual disability and autism. Here we show distinct effects of expression of two major isoforms, long and short, of ZBTB20, and its neurodevelopmental disorder-linked variants, on dendritic architecture of cultured rat cortical pyramidal neurons. The N-terminal of ZBTB20 showed a role in regulating dendritic spine morphology. Two ZBTB20 single nucleotide variants, located at the N-terminal and central regions of the protein and potentially conferring autism risk, altered dendritic spine morphology. In contrast, a single nucleotide variant identified in patients with intellectual disability and located at the C-terminus of ZBTB20 affected dendritic arborization and dendritic length but had no effect on dendritic spine morphology. Furthermore, truncation of the extreme C-terminus of ZBTB20 caused spine and dendritic morphological changes that were similar but distinct from those caused by the C-terminal variant. Taken together, our study suggests ZBTB20's role in dendritic and synaptic structure and provide possible mechanisms of its effect in neurodevelopmental disorders.
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Affiliation(s)
- Kelly A. Jones
- Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - Yue Luo
- J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina, United States of America
| | - Lynn Dukes-Rimsky
- J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina, United States of America
| | - Deepak P. Srivastava
- Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - Richa Koul-Tewari
- J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina, United States of America
- Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, United States of America
| | - Theron A. Russell
- Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - Lauren P. Shapiro
- Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - Anand K. Srivastava
- J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina, United States of America
- Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, United States of America
- * E-mail: (PP); (AKS)
| | - Peter Penzes
- Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
- Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
- * E-mail: (PP); (AKS)
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26
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Guo X, Li M, Gao P, Cao G, Cheng Z, Zhang W, Liu J, Liu X, Li B. Novel splice isoforms of pig myoneurin and their diverse mRNA expression patterns. ASIAN-AUSTRALASIAN JOURNAL OF ANIMAL SCIENCES 2018; 31:1581-1590. [PMID: 29747493 PMCID: PMC6127594 DOI: 10.5713/ajas.17.0911] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/17/2017] [Revised: 02/21/2018] [Accepted: 04/23/2018] [Indexed: 01/24/2023]
Abstract
OBJECTIVE The aim of this study was to clone alternative splicing isoforms of pig myoneurin (MYNN), predict the structure and function of coding protein, and study temporal and spatial expression characteristics of each transcript. METHODS Alternative splice isoforms of MYNN were identified using RNA sequencing (RNA-seq) and cloning techniques. Quantitative real-time polymerase chain reaction (qPCR) was employed to detect expression patterns in 11 tissues of Large White (LW) and Mashen (MS) pigs, and to study developmental expression patterns in cerebellum (CE), stomach (ST), and longissimus dorsi (LD). RESULTS The results showed that MYNN had two alternatively spliced isoforms, MYNN-1 (GenBank accession number: KY470829) and MYNN-2 (GenBank accession number: KY670835). MYNN-1 coding sequence (CDS) is composed of 1,830 bp encoding 609 AA, whereas MYNN-2 CDS is composed of 1,746 bp encoding 581 AA. MYNN-2 was 84 bp less than MYNN-1 and lacked the sixth exon. MYNN-2 was found to have one C2H2 type zinc finger protein domain less than MYNN-1. Two variants were ubiquitously expressed in all pig tissues, and there were significant differences in expression of different tissues (p<0.05; p<0.01). The expression of MYNN-1 was significantly higher than that of MYNN-2 in almost tissues (p<0.05; p<0.01), which testified that MYNN-1 is the main variant. The expression of two isoforms decreased gradually with increase of age in ST and CE of MS pig, whereas increased gradually in LW pig. In LD, the expression of two isoforms increased first and then decreased with increase of age in MS pig, and decreased gradually in LW pig. CONCLUSION Two transcripts of pig MYNN were successfully cloned and MYNN-1 was main variant. MYNN was highly expressed in ST, CE, and LD, and their expression was regular. We speculated that MYNN plays important roles in digestion/absorption and skeletal muscle growth, whereas the specific mechanisms require further elucidation.
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Affiliation(s)
- Xiaohong Guo
- College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi 030801, China
| | - Meng Li
- College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi 030801, China
| | - Pengfei Gao
- College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi 030801, China
| | - Guoqing Cao
- College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi 030801, China
| | - Zhimin Cheng
- College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi 030801, China
| | - Wanfeng Zhang
- College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi 030801, China
| | - Jianfeng Liu
- Key Laboratory of Animal Genetics Breeding and Reproduction, Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Xiaojun Liu
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450002, China
| | - Bugao Li
- College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi 030801, China
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27
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Wang L, Pittman KJ, Barker JR, Salinas RE, Stanaway IB, Williams GD, Carroll RJ, Balmat T, Ingham A, Gopalakrishnan AM, Gibbs KD, Antonia AL, Heitman J, Lee SC, Jarvik GP, Denny JC, Horner SM, DeLong MR, Valdivia RH, Crosslin DR, Ko DC. An Atlas of Genetic Variation Linking Pathogen-Induced Cellular Traits to Human Disease. Cell Host Microbe 2018; 24:308-323.e6. [PMID: 30092202 PMCID: PMC6093297 DOI: 10.1016/j.chom.2018.07.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 05/28/2018] [Accepted: 07/05/2018] [Indexed: 12/18/2022]
Abstract
Pathogens have been a strong driving force for natural selection. Therefore, understanding how human genetic differences impact infection-related cellular traits can mechanistically link genetic variation to disease susceptibility. Here we report the Hi-HOST Phenome Project (H2P2): a catalog of cellular genome-wide association studies (GWAS) comprising 79 infection-related phenotypes in response to 8 pathogens in 528 lymphoblastoid cell lines. Seventeen loci surpass genome-wide significance for infection-associated phenotypes ranging from pathogen replication to cytokine production. We combined H2P2 with clinical association data from patients to identify a SNP near CXCL10 as a risk factor for inflammatory bowel disease. A SNP in the transcriptional repressor ZBTB20 demonstrated pleiotropy, likely through suppression of multiple target genes, and was associated with viral hepatitis. These data are available on a web portal to facilitate interpreting human genome variation through the lens of cell biology and should serve as a rich resource for the research community.
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Affiliation(s)
- Liuyang Wang
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Kelly J Pittman
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Jeffrey R Barker
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Raul E Salinas
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Ian B Stanaway
- Department of Biomedical Informatics and Medical Education, School of Medicine, University of Washington, Seattle, WA 98195, USA
| | - Graham D Williams
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Robert J Carroll
- Department of Biomedical Informatics, School of Medicine, Vanderbilt University, Nashville, TN 37212, USA
| | - Tom Balmat
- Social Science Research Institute, Duke University, Durham, NC 27710, USA
| | - Andy Ingham
- Duke Research Computing, Duke University, Durham, NC 27710, USA
| | - Anusha M Gopalakrishnan
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Kyle D Gibbs
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Alejandro L Antonia
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Joseph Heitman
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA; Division of Infectious Diseases, Department of Medicine, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Soo Chan Lee
- South Texas Center for Emerging Infectious Diseases (STCEID), Department of Biology, College of Sciences, the University of Texas at San Antonio, San Antonio, TX 78249, USA
| | - Gail P Jarvik
- Department of Medicine, Division of Medical Genetics, School of Medicine, University of Washington, Seattle, WA 98195, USA
| | - Joshua C Denny
- Department of Biomedical Informatics, School of Medicine, Vanderbilt University, Nashville, TN 37212, USA
| | - Stacy M Horner
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA; Division of Infectious Diseases, Department of Medicine, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Mark R DeLong
- Duke Research Computing, Duke University, Durham, NC 27710, USA
| | - Raphael H Valdivia
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
| | - David R Crosslin
- Department of Biomedical Informatics and Medical Education, School of Medicine, University of Washington, Seattle, WA 98195, USA
| | - Dennis C Ko
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA; Division of Infectious Diseases, Department of Medicine, School of Medicine, Duke University, Durham, NC 27710, USA.
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28
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Stellacci E, Steindl K, Joset P, Mercurio L, Anselmi M, Cecchetti S, Gogoll L, Zweier M, Hackenberg A, Bocchinfuso G, Stella L, Tartaglia M, Rauch A. Clinical and functional characterization of two novel ZBTB20
mutations causing Primrose syndrome. Hum Mutat 2018; 39:959-964. [DOI: 10.1002/humu.23546] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 04/23/2018] [Accepted: 04/26/2018] [Indexed: 12/20/2022]
Affiliation(s)
- Emilia Stellacci
- Dipartimento di Oncologia e Medicina Molecolare; Istituto Superiore di Sanità; Rome Italy
| | - Katharina Steindl
- Institute of Medical Genetics; University of Zurich; Schlieren-Zurich; Switzerland
| | - Pascal Joset
- Institute of Medical Genetics; University of Zurich; Schlieren-Zurich; Switzerland
| | - Laura Mercurio
- Dipartimento di Oncologia e Medicina Molecolare; Istituto Superiore di Sanità; Rome Italy
| | - Massimiliano Anselmi
- Dipartimento di Scienze e Tecnologie Chimiche; Università di Roma ‘‘Tor Vergata,’’ Rome; Italy
| | - Serena Cecchetti
- Servizio grandi strumentazioni e core facilities; Istituto Superiore di Sanità; Rome Italy
| | - Laura Gogoll
- Institute of Medical Genetics; University of Zurich; Schlieren-Zurich; Switzerland
| | - Markus Zweier
- Institute of Medical Genetics; University of Zurich; Schlieren-Zurich; Switzerland
| | - Annette Hackenberg
- Division of Paediatric Neurology; University Children's Hospital Zurich; Zürich Switzerland
| | - Gianfranco Bocchinfuso
- Dipartimento di Scienze e Tecnologie Chimiche; Università di Roma ‘‘Tor Vergata,’’ Rome; Italy
| | - Lorenzo Stella
- Dipartimento di Scienze e Tecnologie Chimiche; Università di Roma ‘‘Tor Vergata,’’ Rome; Italy
| | - Marco Tartaglia
- Genetics and Rare Diseases Research Division; Ospedale Pediatrico Bambino Gesù; Rome Italy
| | - Anita Rauch
- Institute of Medical Genetics; University of Zurich; Schlieren-Zurich; Switzerland
- radiz-Rare Disease Initiative Zürich; Clinical Research Priority Program for Rare Diseases University of Zurich; Zurich Switzerland
- Neuroscience Center Zurich; University of Zurich and ETH Zurich; Zurich Switzerland
- Zurich Center for Integrative Human Physiology; University of Zurich; Zurich Switzerland
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29
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Zbtb20 Regulates Developmental Neurogenesis in the Olfactory Bulb and Gliogenesis After Adult Brain Injury. Mol Neurobiol 2018; 56:567-582. [DOI: 10.1007/s12035-018-1104-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 05/03/2018] [Indexed: 01/02/2023]
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Abstract
The evolutionary relationships of the mammalian neocortex and avian dorsal telencephalon (DT) nuclei have been debated for more than a century. Despite their central importance to this debate, nonavian reptiles remain underexplored with modern molecular techniques. Reptile studies harbor great potential for understanding the changes in DT organization that occurred in the early evolution of amniotes. They may also help clarify the specializations in the avian DT, which comprises a massive, cell-dense dorsal ventricular ridge (DVR) and a nuclear dorsal-most structure, the Wulst. Crocodilians are phylogenetically and anatomically attractive for DT comparative studies: they are the closest living relatives of birds and have a strikingly bird-like DVR, but they also possess a highly differentiated reptile cerebral cortex. We studied the DT of the American alligator, Alligator mississippiensis, at late embryonic stages with a panel of molecular marker genes. Gene expression and cytoarchitectonic analyses identified clear homologs of all major avian DVR subdivisions including a mesopallium, an extensive nidopallium with primary sensory input territories, and an arcopallium. The alligator medial cortex is divided into three components that resemble the mammalian dentate gyrus, CA fields, and subiculum in gene expression and topography. The alligator dorsal cortex contains putative homologs of neocortical input, output, and intratelencephalic projection neurons and, most notably, these are organized into sublayers similar to mammalian neocortical layers. Our findings on the molecular anatomy of the crocodilian DT are summarized in an atlas of the alligator telencephalon.
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Affiliation(s)
- Steven D Briscoe
- Committee on Development, Regeneration, and Stem Cell Biology, University of Chicago, Chicago, Illinois
| | - Clifton W Ragsdale
- Committee on Development, Regeneration, and Stem Cell Biology, University of Chicago, Chicago, Illinois.,Department of Neurobiology, University of Chicago, Chicago, Illinois.,Department of Organismal Biology and Anatomy, University of Chicago, Chicago, Illinois
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31
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Kan H, Huang Y, Li X, Liu D, Chen J, Shu M. Zinc finger protein ZBTB20 is an independent prognostic marker and promotes tumor growth of human hepatocellular carcinoma by repressing FoxO1. Oncotarget 2017; 7:14336-49. [PMID: 26893361 PMCID: PMC4924719 DOI: 10.18632/oncotarget.7425] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2015] [Accepted: 01/29/2016] [Indexed: 12/17/2022] Open
Abstract
Zinc finger and BTB domain-containing 20 (ZBTB20) is a new BTB/POZ-domain gene and a member of the POK family of transcriptional repressors. Notably, the role of ZBTB20 and its underlying mechanisms involved in hepatocarcinogenesis are poorly investigated. In this study, the expression of ZBTB20 was significantly overexpressed in hepatocellular carcinoma (HCC) tissues. The positive expression of ZBTB20 was associated with large tumor size, high Edmondson-Steiner grading and advanced tumor-node-metastasis (TNM) tumor stage. Additionally, HCC patients with positive expression of ZBTB20 had a poorer 5-year survival. Multivariate analyses revealed that ZBTB20 overexpression was an independent prognostic factor for HCC. Gain- and loss-of-function experiments demonstrated that ZBTB20 promoted HCC cell viability, proliferation, tumorigenicity, and cell cycle progression. Mechanistically, Cyclin D1 and Cyclin E were increased, while p21 and p27 were decreased by ZBTB20 in HCC cells. FoxO1 was inversely correlated with ZBTB20 protein expression in the same cohort of HCC specimens. We further revealed that FoxO1 was transcriptionally repressed by ZBTB20 in HCC. Moreover, restoration of FoxO1 expression partially abrogated ZBTB20-induced HCC cell proliferation and growth entry in vitro and in vivo. Collectively, these results indicate that ZBTB20 may serve as a prognostic marker and promotes tumor growth of HCC via transcriptionally repressing FoxO1.
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Affiliation(s)
- Heping Kan
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yuqi Huang
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Xianghong Li
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Dingli Liu
- Department of Infectious Disease, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jianjia Chen
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Miaojiang Shu
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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32
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Casertano A, Fontana P, Hennekam RC, Tartaglia M, Genesio R, Dieber TB, Ortega L, Nitsch L, Melis D. Alterations in metabolic patterns have a key role in diagnosis and progression of primrose syndrome. Am J Med Genet A 2017; 173:1896-1902. [DOI: 10.1002/ajmg.a.38124] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 11/18/2016] [Accepted: 12/09/2016] [Indexed: 12/19/2022]
Affiliation(s)
- Alberto Casertano
- Department of Translational Medical Sciences; Section of Pediatrics; Federico II University; Naples Italy
| | - Paolo Fontana
- Department of Molecular Medicine and Medical Biotechnology; Federico II University; Naples Italy
| | - Raoul C. Hennekam
- Department of Pediatrics; Academic Medical Center; University of Amsterdam; Amsterdam the Netherlands
| | - Marco Tartaglia
- Genetics and Rare Diseases Research Division; Ospedale pediatrico Bambino Gesù; Rome Italy
| | - Rita Genesio
- Department of Molecular Medicine and Medical Biotechnology; Federico II University; Naples Italy
| | | | | | - Lucio Nitsch
- Department of Molecular Medicine and Medical Biotechnology; Federico II University; Naples Italy
| | - Daniela Melis
- Department of Translational Medical Sciences; Section of Pediatrics; Federico II University; Naples Italy
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33
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Qu Z, Zhang H, Huang M, Shi G, Liu Z, Xie P, Li H, Wang W, Xu G, Zhang Y, Yang L, Huang G, Takahashi JS, Zhang WJ, Xu Y. Loss of ZBTB20 impairs circadian output and leads to unimodal behavioral rhythms. eLife 2016; 5:e17171. [PMID: 27657167 PMCID: PMC5033604 DOI: 10.7554/elife.17171] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 09/01/2016] [Indexed: 12/15/2022] Open
Abstract
Many animals display morning and evening bimodal activities in the day/night cycle. However, little is known regarding the potential components involved in the regulation of bimodal behavioral rhythms in mammals. Here, we identified that the zinc finger protein gene Zbtb20 plays a crucial role in the regulation of bimodal activities in mice. Depletion of Zbtb20 in nerve system resulted in the loss of early evening activity, but the increase of morning activity. We found that Zbtb20-deficient mice exhibited a pronounced decrease in the expression of Prokr2 and resembled phenotypes of Prok2 and Prokr2-knockout mice. Injection of adeno-associated virus-double-floxed Prokr2 in suprachiasmatic nucleus could partly restore evening activity in Nestin-Cre; Zbtb20fl/fl (NS-ZB20KO) mice. Furthermore, loss of Zbtb20 in Foxg1 loci, but intact in the suprachiasmatic nucleus, was not responsible for the unimodal activity of NS-ZB20KO mice. Our study provides evidence that ZBTB20-mediated PROKR2 signaling is critical for the evening behavioral rhythms.
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Affiliation(s)
- Zhipeng Qu
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China
| | - Hai Zhang
- Department of Pathophysiology, Second Military Medical University, Shanghai, China
| | - Moli Huang
- Cambridge-Suda Genomic Research Center, Soochow University, Suzhou, China
| | - Guangsen Shi
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China
| | - Zhiwei Liu
- Cambridge-Suda Genomic Research Center, Soochow University, Suzhou, China
| | - Pancheng Xie
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China
| | - Hui Li
- Department of Pathophysiology, Second Military Medical University, Shanghai, China
| | - Wei Wang
- Cambridge-Suda Genomic Research Center, Soochow University, Suzhou, China
| | - Guoqiang Xu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Yang Zhang
- Cambridge-Suda Genomic Research Center, Soochow University, Suzhou, China
| | - Ling Yang
- Cambridge-Suda Genomic Research Center, Soochow University, Suzhou, China
| | - Guocun Huang
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
| | - Joseph S Takahashi
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
| | - Weiping J Zhang
- Department of Pathophysiology, Second Military Medical University, Shanghai, China
| | - Ying Xu
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China
- Cambridge-Suda Genomic Research Center, Soochow University, Suzhou, China
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34
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Saavedra K, Molina-Márquez AM, Saavedra N, Zambrano T, Salazar LA. Epigenetic Modifications of Major Depressive Disorder. Int J Mol Sci 2016; 17:ijms17081279. [PMID: 27527165 PMCID: PMC5000676 DOI: 10.3390/ijms17081279] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Revised: 07/24/2016] [Accepted: 07/29/2016] [Indexed: 12/17/2022] Open
Abstract
Major depressive disorder (MDD) is a chronic disease whose neurological basis and pathophysiology remain poorly understood. Initially, it was proposed that genetic variations were responsible for the development of this disease. Nevertheless, several studies within the last decade have provided evidence suggesting that environmental factors play an important role in MDD pathophysiology. Alterations in epigenetics mechanism, such as DNA methylation, histone modification and microRNA expression could favor MDD advance in response to stressful experiences and environmental factors. The aim of this review is to describe genetic alterations, and particularly altered epigenetic mechanisms, that could be determinants for MDD progress, and how these alterations may arise as useful screening, diagnosis and treatment monitoring biomarkers of depressive disorders.
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Affiliation(s)
- Kathleen Saavedra
- Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus, Universidad de La Frontera, Temuco 4811230, Chile.
| | - Ana María Molina-Márquez
- Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus, Universidad de La Frontera, Temuco 4811230, Chile.
| | - Nicolás Saavedra
- Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus, Universidad de La Frontera, Temuco 4811230, Chile.
| | - Tomás Zambrano
- Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus, Universidad de La Frontera, Temuco 4811230, Chile.
| | - Luis A Salazar
- Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus, Universidad de La Frontera, Temuco 4811230, Chile.
- Millennium Institute for Research in Depression and Personality (MIDAP), Universidad de La Frontera, Temuco 4811230, Chile.
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35
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Alonso-Martin S, Rochat A, Mademtzoglou D, Morais J, de Reyniès A, Auradé F, Chang THT, Zammit PS, Relaix F. Gene Expression Profiling of Muscle Stem Cells Identifies Novel Regulators of Postnatal Myogenesis. Front Cell Dev Biol 2016; 4:58. [PMID: 27446912 PMCID: PMC4914952 DOI: 10.3389/fcell.2016.00058] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 06/02/2016] [Indexed: 01/02/2023] Open
Abstract
Skeletal muscle growth and regeneration require a population of muscle stem cells, the satellite cells, located in close contact to the myofiber. These cells are specified during fetal and early postnatal development in mice from a Pax3/7 population of embryonic progenitor cells. As little is known about the genetic control of their formation and maintenance, we performed a genome-wide chronological expression profile identifying the dynamic transcriptomic changes involved in establishment of muscle stem cells through life, and acquisition of muscle stem cell properties. We have identified multiple genes and pathways associated with satellite cell formation, including set of genes specifically induced (EphA1, EphA2, EfnA1, EphB1, Zbtb4, Zbtb20) or inhibited (EphA3, EphA4, EphA7, EfnA2, EfnA3, EfnA4, EfnA5, EphB2, EphB3, EphB4, EfnBs, Zfp354c, Zcchc5, Hmga2) in adult stem cells. Ephrin receptors and ephrins ligands have been implicated in cell migration and guidance in many tissues including skeletal muscle. Here we show that Ephrin receptors and ephrins ligands are also involved in regulating the adult myogenic program. Strikingly, impairment of EPHB1 function in satellite cells leads to increased differentiation at the expense of self-renewal in isolated myofiber cultures. In addition, we identified new transcription factors, including several zinc finger proteins. ZFP354C and ZCCHC5 decreased self-renewal capacity when overexpressed, whereas ZBTB4 increased it, and ZBTB20 induced myogenic progression. The architectural and transcriptional regulator HMGA2 was involved in satellite cell activation. Together, our study shows that transcriptome profiling coupled with myofiber culture analysis, provides an efficient system to identify and validate candidate genes implicated in establishment/maintenance of muscle stem cells. Furthermore, tour de force transcriptomic profiling provides a wealth of data to inform for future stem cell-based muscle therapies.
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Affiliation(s)
- Sonia Alonso-Martin
- Institut Mondor de Recherche Biomédicale, INSERM U955-E10Créteil, France; Université Paris Est, Faculté de MedecineCréteil, France; Ecole Nationale Veterinaire d'AlfortMaison Alfort, France
| | - Anne Rochat
- Institut Mondor de Recherche Biomédicale, INSERM U955-E10 Créteil, France
| | - Despoina Mademtzoglou
- Institut Mondor de Recherche Biomédicale, INSERM U955-E10Créteil, France; Université Paris Est, Faculté de MedecineCréteil, France; Ecole Nationale Veterinaire d'AlfortMaison Alfort, France
| | - Jessica Morais
- Institut Mondor de Recherche Biomédicale, INSERM U955-E10 Créteil, France
| | - Aurélien de Reyniès
- Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer Paris, France
| | - Frédéric Auradé
- Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, Center for Research in Myology Paris, France
| | - Ted Hung-Tse Chang
- Institut Mondor de Recherche Biomédicale, INSERM U955-E10 Créteil, France
| | - Peter S Zammit
- Randall Division of Cell and Molecular Biophysics, King's College London London, UK
| | - Frédéric Relaix
- Institut Mondor de Recherche Biomédicale, INSERM U955-E10Créteil, France; Université Paris Est, Faculté de MedecineCréteil, France; Ecole Nationale Veterinaire d'AlfortMaison Alfort, France; Etablissement Français du SangCréteil, France; APHP, Hopitaux Universitaires Henri Mondor, DHU Pepsy and Centre de Référence des Maladies Neuromusculaires GNMHCréteil, France
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36
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Tonchev AB, Tuoc TC, Rosenthal EH, Studer M, Stoykova A. Zbtb20 modulates the sequential generation of neuronal layers in developing cortex. Mol Brain 2016; 9:65. [PMID: 27282384 PMCID: PMC4901408 DOI: 10.1186/s13041-016-0242-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 05/21/2016] [Indexed: 11/25/2022] Open
Abstract
Background During corticogenesis, genetic programs encoded in progenitor cells at different developmental stages and inherited in postmitotic neurons specify distinct layer and area identities. Transcription factor Zbtb20 has been shown to play a role for hippocampal development but whether it is implicated in mammalian neocortical morphogenesis remains unknown. Results Here, we report that during embyogenesis transcription factor Zbtb20 has a dynamic spatio-temporal expression pattern in mitotic cortical progenitors through which it modulates the sequential generation of cortical neuronal layer identities. Zbtb20 knock out mice exhibited enhanced populations of early born L6-L4 neuronal subtypes and a dramatic reduction of the late born L3/L2 neurons. This defect was due to a temporal misbalance in the production of earlier versus later born neurons, leading to a progressive diminishing of the progenitor pool for the generation of L3-L2 neurons. Zbtb20 implements these temporal effects in part by binding to promoter of the orphan nuclear receptor CoupTF1/Nr2f1. In addition to its effects exerted in cortical progenitors, the postmitotic expression of Zbtb20 in L3/L2 neurons starting at birth may contribute to their proper differentiation and migration. Conclusions Our findings reveal Zbtb20 as a novel temporal regulator for the generation of layer-specific neuronal identities. Electronic supplementary material The online version of this article (doi:10.1186/s13041-016-0242-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Anton B Tonchev
- Molecular Developmental Neurobiology Laboratory, Max Planck Institute of Biophysical Chemistry, Am Fassberg, 37077, Gottingen, Germany. .,Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37075, Göttingen, Germany. .,Department of Anatomy, Histology and Embryology, Medical University-Varna, Varna, Bulgaria.
| | - Tran Cong Tuoc
- Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37075, Göttingen, Germany.,Molecular Neurobiology Group, Institute of Neuroanatomy, University of Goettingen Medical Center, Goettingen, Germany
| | - Eva H Rosenthal
- Molecular Developmental Neurobiology Laboratory, Max Planck Institute of Biophysical Chemistry, Am Fassberg, 37077, Gottingen, Germany
| | - Michèle Studer
- University Nice Sophia Antipolis, iBV, UMR 7277, F-06108, Nice, France.,Inserm, iBV, U1091, F-06108, Nice, France
| | - Anastassia Stoykova
- Molecular Developmental Neurobiology Laboratory, Max Planck Institute of Biophysical Chemistry, Am Fassberg, 37077, Gottingen, Germany. .,Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37075, Göttingen, Germany. .,Department of Anatomy, Histology and Embryology, Medical University-Varna, Varna, Bulgaria.
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37
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Zbtb20 promotes astrocytogenesis during neocortical development. Nat Commun 2016; 7:11102. [PMID: 27000654 PMCID: PMC4804180 DOI: 10.1038/ncomms11102] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Accepted: 02/19/2016] [Indexed: 11/08/2022] Open
Abstract
Multipotent neural precursor cells (NPCs) generate astrocytes at late stages of mammalian neocortical development. Many signalling pathways that regulate astrocytogenesis directly induce the expression of GFAP, a marker of terminally differentiated astrocytes. However, astrocyte specification occurs before GFAP expression and essential factors for the specification step have remained elusive. Here we show that Zbtb20 regulates astrocyte specification in the mouse neocortex. Zbtb20 is highly expressed in late-stage NPCs and their astrocytic progeny. Overexpression and knockdown of Zbtb20 promote and suppress astrocytogenesis, respectively, although Zbtb20 does not directly activate the Gfap promoter. Astrocyte induction by Zbtb20 is suppressed by knockdown of Sox9 or NFIA. Furthermore, in the astrocyte lineage, Zbtb20 directly represses the expression of Brn2, which encodes a protein necessary for upper-layer neuron specification. Zbtb20 is thus a key determinant of astrocytogenesis, in which it collaborates with Sox9 and NFIA, and acts in part through direct repression of Brn2 expression. Astrocytes in the brain are derived from neural precursor cells (NPCs). Here, Motoshi Nagao and colleagues show that the transcription repressor Zbtb20 regulates astrocyte specification in the mouse neocortex.
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Sterlin D, Velasco G, Moshous D, Touzot F, Mahlaoui N, Fischer A, Suarez F, Francastel C, Picard C. Genetic, Cellular and Clinical Features of ICF Syndrome: a French National Survey. J Clin Immunol 2016; 36:149-59. [PMID: 26851945 DOI: 10.1007/s10875-016-0240-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Accepted: 01/31/2016] [Indexed: 12/22/2022]
Abstract
PURPOSE Autosomal recessive deficiencies of DNMT3B or ZBTB24 account for two-thirds of cases of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome). This primary immunodeficiency (PID) is characterized mainly by an antibody deficiency, facial abnormalities and centromeric instability. We analyzed the national cohort of patients with ICF syndrome with the aim of providing a more detailed description of the phenotype and management of patients with ICF syndrome. METHODS Demographic, genetic, immunological, and clinical features were recorded for each patient. RESULTS In the French cohort, seven of the nine patients carried DNMT3B mutations, six of which had never been described before. One patient had compound heterozygous ZBTB24 mutations. All patients were found to lack CD19(+)CD27(+) memory B cells. This feature is a major diagnostic criterion for both ICF1 and ICF2. Patients suffered both bacterial and viral infections, and three patients developed bronchiectasis. Autoimmune manifestations (hepatitis, nephritis and thyroiditis) not previously reported in ICF1 patients were also detected in two of our ICF1 patients. The mode of treatment and outcome of the French patients are reported, by genetic defect, and compared with those for 68 previously reported ICF patients. Immunoglobulin (Ig) replacement treatment was administered to all nine French patients. One ICF1 patient presented severe autoimmune manifestations and pancytopenia and underwent allogeneic hematopoietic stem cell transplantation (HSCT), but she died from unknown causes 6 years post-transplant. CONCLUSION Autoimmune signs are uncommon in ICF syndrome, but, when present, they affect patient outcome and require immunosuppressive treatment. The long-term outcome of ICF patients has been improved by the combination of IgG replacement and antibiotic prophylaxis.
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Affiliation(s)
- Delphine Sterlin
- Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris (APHP), University Paris Descartes, 149 rue de Sevres, 75015, Paris, France
| | - Guillaume Velasco
- CNRS UMR7216, Epigenetics and Cell Fate, Sorbonne Paris Cité, Université Paris Diderot, Paris, France
| | - Despina Moshous
- Pediatric Immuno-Hematology Unit, Necker Children's Hospital, APHP, Université Paris Descartes, Paris, France.,INSERM UMR1163, Imagine Institute, Necker Medical School, Sorbonne Paris Cité, University Paris Descartes, Paris, France
| | - Fabien Touzot
- Pediatric Immuno-Hematology Unit, Necker Children's Hospital, APHP, Université Paris Descartes, Paris, France.,INSERM UMR1163, Imagine Institute, Necker Medical School, Sorbonne Paris Cité, University Paris Descartes, Paris, France.,Laboratory of Molecular Mechanisms of Hematologic Disorders and Therapeutic Implications, INSERM UMR1163, Imagine Institut, Necker Medical School, University Paris Descartes, Paris, France.,Biotherapy Department, Necker-Enfants Malades Hospital, APHP, University Paris Descartes, Paris, France
| | - Nizar Mahlaoui
- Pediatric Immuno-Hematology Unit, Necker Children's Hospital, APHP, Université Paris Descartes, Paris, France.,French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker - Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Alain Fischer
- Pediatric Immuno-Hematology Unit, Necker Children's Hospital, APHP, Université Paris Descartes, Paris, France.,INSERM UMR1163, Imagine Institute, Necker Medical School, Sorbonne Paris Cité, University Paris Descartes, Paris, France.,College de France, Paris, France.,French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker - Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Felipe Suarez
- Adult Hematology Unit, Necker Children's Hospital, APHP, University Paris Descartes, Paris, France.,French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker - Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.,INSERM UMR1163 and CNRS ERL8254, Imagine Institute, Necker Medical School, Sorbonne Paris Cité, University Paris Descartes, Paris, France
| | - Claire Francastel
- CNRS UMR7216, Epigenetics and Cell Fate, Sorbonne Paris Cité, Université Paris Diderot, Paris, France
| | - Capucine Picard
- Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris (APHP), University Paris Descartes, 149 rue de Sevres, 75015, Paris, France. .,Pediatric Immuno-Hematology Unit, Necker Children's Hospital, APHP, Université Paris Descartes, Paris, France. .,Laboratory of the Human Genetics of Infectious Diseases, INSERM UMR1163, Imagine Institute, Necker Medical School, Sorbonne Paris Cité, University Paris Descartes, Paris, France. .,French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker - Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.
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Smith SM, Carew NT, Milcarek C. RNA polymerases in plasma cells trav-ELL2 the beat of a different drum. World J Immunol 2015; 5:99-112. [DOI: 10.5411/wji.v5.i3.99] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 08/19/2015] [Accepted: 11/17/2015] [Indexed: 02/05/2023] Open
Abstract
There is a major transformation in gene expression between mature B cells (including follicular, marginal zone, and germinal center cells) and antibody secreting cells (ASCs), i.e., ASCs, (including plasma blasts, splenic plasma cells, and long-lived bone marrow plasma cells). This significant change-over occurs to accommodate the massive amount of secretory-specific immunoglobulin that ASCs make and the export processes itself. It is well known that there is an up-regulation of a small number of ASC-specific transcription factors Prdm1 (B-lymphocyte-induced maturation protein 1), interferon regulatory factor 4, and Xbp1, and the reciprocal down-regulation of Pax5, Bcl6 and Bach2, which maintain the B cell program. Less well appreciated are the major alterations in transcription elongation and RNA processing occurring between B cells and ASCs. The three ELL family members ELL1, 2 and 3 have different protein sequences and potentially distinct cellular roles in transcription elongation. ELL1 is involved in DNA repair and small RNAs while ELL3 was previously described as either testis or stem-cell specific. After B cell stimulation to ASCs, ELL3 levels fall precipitously while ELL1 falls off slightly. ELL2 is induced at least 10-fold in ASCs relative to B cells. All of these changes cause the RNA Polymerase II in ASCs to acquire different properties, leading to differences in RNA processing and histone modifications.
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Zhou G, Jiang X, Zhang H, Lu Y, Liu A, Ma X, Yang G, Yang R, Shen H, Zheng J, Hu Y, Yang X, Zhang WJ, Xie Z. Zbtb20 regulates the terminal differentiation of hypertrophic chondrocytes via repression of Sox9. Development 2015; 142:385-93. [DOI: 10.1242/dev.108530] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The terminal differentiation of hypertrophic chondrocytes is a tightly regulated process that plays a pivotal role in endochondral ossification. As a negative regulator, Sox9 is essentially downregulated in terminally differentiated hypertrophic chondrocytes. However, the underlying mechanism of Sox9 silencing is undefined. Here we show that the zinc finger protein Zbtb20 regulates the terminal differentiation of hypertrophic chondrocytes by repressing Sox9. In the developing skeleton of the mouse, Zbtb20 protein is highly expressed by hypertrophic chondrocytes from late embryonic stages. To determine its physiological role in endochondral ossification, we have generated chondrocyte-specific Zbtb20 knockout mice and demonstrate that disruption of Zbtb20 in chondrocytes results in delayed endochondral ossification and postnatal growth retardation. Zbtb20 deficiency caused a delay in cartilage vascularization and an expansion of the hypertrophic zone owing to reduced expression of Vegfa in the hypertrophic zone. Interestingly, Sox9, a direct suppressor of Vegfa expression, was ectopically upregulated at both mRNA and protein levels in the late Zbtb20-deficient hypertrophic zone. Furthermore, knockdown of Sox9 greatly increased Vegfa expression in Zbtb20-deficient hypertrophic chondrocytes. Our findings point to Zbtb20 as a crucial regulator governing the terminal differentiation of hypertrophic chondrocytes at least partially through repression of Sox9.
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Affiliation(s)
- Guangdi Zhou
- Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China
- Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China
| | - Xuchao Jiang
- Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China
- Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China
| | - Hai Zhang
- Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China
- Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China
| | - Yinzhong Lu
- Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China
| | - Anjun Liu
- Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China
- Department of Cell Biology, Second Military Medical University, Shanghai 200433, China
| | - Xianhua Ma
- Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China
| | - Guan Yang
- Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing 100071, China
| | - Rui Yang
- Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China
| | - Hongxing Shen
- Department of Orthopedics, Changhai Hospital, Shanghai 200433, China
| | - Jianming Zheng
- Department of Pathology, Changhai Hospital, Shanghai 200433, China
| | - Yiping Hu
- Department of Cell Biology, Second Military Medical University, Shanghai 200433, China
| | - Xiao Yang
- Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing 100071, China
| | - Weiping J. Zhang
- Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China
| | - Zhifang Xie
- Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China
- Department of Cell Biology, Second Military Medical University, Shanghai 200433, China
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Ren AJ, Wang K, Zhang H, Liu A, Ma X, Liang Q, Cao D, Wood JN, He DZ, Ding YQ, Yuan WJ, Xie Z, Zhang WJ. ZBTB20 regulates nociception and pain sensation by modulating TRP channel expression in nociceptive sensory neurons. Nat Commun 2014; 5:4984. [PMID: 25369838 PMCID: PMC6687506 DOI: 10.1038/ncomms5984] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 08/14/2014] [Indexed: 12/21/2022] Open
Abstract
In mammals, pain sensation is initiated by the detection of noxious stimuli through specialized transduction ion channels and receptors in nociceptive sensory neurons. Transient receptor potential (TRP) channels are the key sensory transducers that confer nociceptors distinct sensory modalities. However, the regulatory mechanisms about their expression are poorly defined. Here we show that the zinc-finger protein ZBTB20 regulates TRP channels expression in nociceptors. ZBTB20 is highly expressed in nociceptive sensory neurons of dorsal root ganglia. Disruption of ZBTB20 in nociceptors led to a marked decrease in the expression levels of TRPV1, TRPA1 and TRPM8 and the response of calcium flux and whole-cell currents evoked by their respective specific agonists. Phenotypically, the mice lacking ZBTB20 specifically in nociceptors showed a defect in nociception and pain sensation in response to thermal, mechanical and inflammatory stimulation. Our findings point to ZBTB20 as a critical regulator of nociception and pain sensation by modulating TRP channels expression in nociceptors.
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Affiliation(s)
- An-Jing Ren
- Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China
| | - Kai Wang
- Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China
| | - Huan Zhang
- Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China
| | - Anjun Liu
- 1] Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China [2] Department of Cell Biology, Second Military Medical University, Shanghai 200433, China
| | - Xianhua Ma
- Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China
| | - Qing Liang
- Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China
| | - Dongmei Cao
- Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China
| | - John N Wood
- Biology Department, University College London, Gower Street, London WC1E 6BT, UK
| | - David Z He
- Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, Nebraska 68102, USA
| | - Yu-Qiang Ding
- Department of Anatomy and Neurobiology, Tongji University School of Medicine, Shanghai 200092, China
| | - Wen-Jun Yuan
- Department of Physiology and Neurobiology, Key Lab of Ministry of Education in Fertility Preservation and Maintenance, Ningxia Medical University, Yinchuan 750004, China
| | - Zhifang Xie
- 1] Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China [2] Department of Cell Biology, Second Military Medical University, Shanghai 200433, China
| | - Weiping J Zhang
- Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China
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Rasmussen MB, Nielsen JV, Lourenço CM, Melo JB, Halgren C, Geraldi CVL, Marques W, Rodrigues GR, Thomassen M, Bak M, Hansen C, Ferreira SI, Venâncio M, Henriksen KF, Lind-Thomsen A, Carreira IM, Jensen NA, Tommerup N. Neurodevelopmental disorders associated with dosage imbalance ofZBTB20correlate with the morbidity spectrum of ZBTB20 candidate target genes. J Med Genet 2014; 51:605-13. [DOI: 10.1136/jmedgenet-2014-102535] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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43
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Mutations in ZBTB20 cause Primrose syndrome. Nat Genet 2014; 46:815-7. [DOI: 10.1038/ng.3035] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Accepted: 06/23/2014] [Indexed: 02/06/2023]
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Chevrier S, Emslie D, Shi W, Kratina T, Wellard C, Karnowski A, Erikci E, Smyth GK, Chowdhury K, Tarlinton D, Corcoran LM. The BTB-ZF transcription factor Zbtb20 is driven by Irf4 to promote plasma cell differentiation and longevity. ACTA ACUST UNITED AC 2014; 211:827-40. [PMID: 24711583 PMCID: PMC4010913 DOI: 10.1084/jem.20131831] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Zbtb20 facilitates terminal differentiation of B cells into antibody-secreting cells, and its expression is dependent on Irf4 and independent of Blimp1. The transcriptional network regulating antibody-secreting cell (ASC) differentiation has been extensively studied, but our current understanding is limited. The mechanisms of action of known “master” regulators are still unclear, while the participation of new factors is being revealed. Here, we identify Zbtb20, a Bcl6 homologue, as a novel regulator of late B cell development. Within the B cell lineage, Zbtb20 is specifically expressed in B1 and germinal center B cells and peaks in long-lived bone marrow (BM) ASCs. Unlike Bcl6, an inhibitor of ASC differentiation, ectopic Zbtb20 expression in primary B cells facilitates terminal B cell differentiation to ASCs. In plasma cell lines, Zbtb20 induces cell survival and blocks cell cycle progression. Immunized Zbtb20-deficient mice exhibit curtailed humoral responses and accelerated loss of antigen-specific plasma cells, specifically from the BM pool. Strikingly, Zbtb20 induction does not require Blimp1 but depends directly on Irf4, acting at a newly identified Zbtb20 promoter in ASCs. These results identify Zbtb20 as an important player in late B cell differentiation and provide new insights into this complex process.
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Affiliation(s)
- Stéphane Chevrier
- Molecular Immunology Division, 2 Bioinformatics Division, 3 Immunology Division, The Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia
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45
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Wang Y, Bhattacharya D. Adjuvant-specific regulation of long-term antibody responses by ZBTB20. ACTA ACUST UNITED AC 2014; 211:841-56. [PMID: 24711582 PMCID: PMC4010912 DOI: 10.1084/jem.20131821] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
ZBTB20 promotes long-lived plasma cell survival after primary activation under alum but not TLR2- and TLR4-activating adjuvant conditions. The duration of antibody production by long-lived plasma cells varies with the type of immunization, but the basis for these differences is unknown. We demonstrate that plasma cells formed in response to the same immunogen engage distinct survival programs depending on the adjuvant. After alum-adjuvanted immunization, antigen-specific bone marrow plasma cells deficient in the transcription factor ZBTB20 failed to accumulate over time, leading to a progressive loss of antibody production relative to wild-type controls. Fetal liver reconstitution experiments demonstrated that the requirement for ZBTB20 was B cell intrinsic. No defects were observed in germinal center numbers, affinity maturation, or plasma cell formation or proliferation in ZBTB20-deficient chimeras. However, ZBTB20-deficient plasma cells expressed reduced levels of MCL1 relative to wild-type controls, and transgenic expression of BCL2 increased serum antibody titers. These data indicate a role for ZBTB20 in promoting survival in plasma cells. Strikingly, adjuvants that activate TLR2 and TLR4 restored long-term antibody production in ZBTB20-deficient chimeras through the induction of compensatory survival programs in plasma cells. Thus, distinct lifespans are imprinted in plasma cells as they are formed, depending on the primary activation conditions. The durability of vaccines may accordingly be improved through the selection of appropriate adjuvants.
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Affiliation(s)
- Yinan Wang
- Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110
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46
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Davies MN, Krause L, Bell JT, Gao F, Ward KJ, Wu H, Lu H, Liu Y, Tsai PC, Collier DA, Murphy T, Dempster E, Mill J, Battle A, Mostafavi S, Zhu X, Henders A, Byrne E, Wray NR, Martin NG, Spector TD, Wang J. Hypermethylation in the ZBTB20 gene is associated with major depressive disorder. Genome Biol 2014; 15:R56. [PMID: 24694013 PMCID: PMC4072999 DOI: 10.1186/gb-2014-15-4-r56] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Accepted: 04/02/2014] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Although genetic variation is believed to contribute to an individual's susceptibility to major depressive disorder, genome-wide association studies have not yet identified associations that could explain the full etiology of the disease. Epigenetics is increasingly believed to play a major role in the development of common clinical phenotypes, including major depressive disorder. RESULTS Genome-wide MeDIP-Sequencing was carried out on a total of 50 monozygotic twin pairs from the UK and Australia that are discordant for depression. We show that major depressive disorder is associated with significant hypermethylation within the coding region of ZBTB20, and is replicated in an independent cohort of 356 unrelated case-control individuals. The twins with major depressive disorder also show increased global variation in methylation in comparison with their unaffected co-twins. ZBTB20 plays an essential role in the specification of the Cornu Ammonis-1 field identity in the developing hippocampus, a region previously implicated in the development of major depressive disorder. CONCLUSIONS Our results suggest that aberrant methylation profiles affecting the hippocampus are associated with major depressive disorder and show the potential of the epigenetic twin model in neuro-psychiatric disease.
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Shuvarikov A, Campbell IM, Dittwald P, Neill NJ, Bialer MG, Moore C, Wheeler PG, Wallace SE, Hannibal MC, Murray MF, Giovanni MA, Terespolsky D, Sodhi S, Cassina M, Viskochil D, Moghaddam B, Herman K, Brown CW, Beck CR, Gambin A, Cheung SW, Patel A, Lamb AN, Shaffer LG, Ellison JW, Ravnan JB, Stankiewicz P, Rosenfeld JA. Recurrent HERV-H-mediated 3q13.2-q13.31 deletions cause a syndrome of hypotonia and motor, language, and cognitive delays. Hum Mutat 2013; 34:1415-23. [PMID: 23878096 DOI: 10.1002/humu.22384] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Accepted: 07/11/2013] [Indexed: 11/09/2022]
Abstract
We describe the molecular and clinical characterization of nine individuals with recurrent, 3.4-Mb, de novo deletions of 3q13.2-q13.31 detected by chromosomal microarray analysis. All individuals have hypotonia and language and motor delays; they variably express mild to moderate cognitive delays (8/9), abnormal behavior (7/9), and autism spectrum disorders (3/9). Common facial features include downslanting palpebral fissures with epicanthal folds, a slightly bulbous nose, and relative macrocephaly. Twenty-eight genes map to the deleted region, including four strong candidate genes, DRD3, ZBTB20, GAP43, and BOC, with important roles in neural and/or muscular development. Analysis of the breakpoint regions based on array data revealed directly oriented human endogenous retrovirus (HERV-H) elements of ~5 kb in size and of >95% DNA sequence identity flanking the deletion. Subsequent DNA sequencing revealed different deletion breakpoints and suggested nonallelic homologous recombination (NAHR) between HERV-H elements as a mechanism of deletion formation, analogous to HERV-I-flanked and NAHR-mediated AZFa deletions. We propose that similar HERV elements may also mediate other recurrent deletion and duplication events on a genome-wide scale. Observation of rare recurrent chromosomal events such as these deletions helps to further the understanding of mechanisms behind naturally occurring variation in the human genome and its contribution to genetic disease.
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Affiliation(s)
- Andrey Shuvarikov
- Signature Genomic Laboratories, PerkinElmer, Inc, Spokane, Washington
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Kucherenko MM, Shcherbata HR. Steroids as external temporal codes act via microRNAs and cooperate with cytokines in differential neurogenesis. Fly (Austin) 2013; 7:173-83. [PMID: 23839338 PMCID: PMC4049850 DOI: 10.4161/fly.25241] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
The generation of neuronal cell diversity is controlled by interdependent mechanisms, including cell intrinsic programs and environmental cues. During development, the astonishing variety of neurons is originated according to a precise timetable that is managed by a complex network of genes specifying individual types of neurons. Different neurons express specific sets of transcription factors, and they can be recognized by morphological characteristics and spatial localization, but, most importantly, they connect to each other and form functional units in a stereotyped fashion. This connectivity depends, mostly, on selective cell adhesion that is strictly regulated. While intrinsic factors specifying neuronal temporal identity have been extensively studied, an extrinsic temporal factor controlling neuronal temporal identity switch has not been shown. Our data demonstrate that pulses of steroid hormone act as a temporal cue to fine-tune neuronal cell differentiation. Here we also provide evidence that extrinsic JAK/STAT cytokine signaling acts as a spatial code in the process. Particularly, in Drosophila mushroom bodies, neuronal identity transition is controlled by steroid-dependent microRNAs that regulate spatially distributed cytokine-dependent signaling factors that in turn modulate cell adhesion. A new era of neuronal plasticity assessment via managing external temporal cues such as hormones and cytokines that specify individual types of neurons might open new possibilities for brain regenerative therapeutics.
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Affiliation(s)
- Mariya M Kucherenko
- Max Planck Research Group of Gene Expression and Signaling; Max Planck Institute for Biophysical Chemistry; Goettingen, Germany
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Zinc finger protein ZBTB20 promotes Toll-like receptor-triggered innate immune responses by repressing IκBα gene transcription. Proc Natl Acad Sci U S A 2013; 110:11097-102. [PMID: 23776228 DOI: 10.1073/pnas.1301257110] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptor (TLR) signaling is critical in innate response against invading pathogens. However, the molecular mechanisms for full activation of TLR-triggered innate immunity need to be fully elucidated. The broad complex tramtrack bric-a-brac/poxvirus and zinc finger (BTB/POZ) family is a class of transcription factors involved in many biological processes. However, few BTB/POZ proteins were reported to function in innate immune response. Zinc finger and BTB domain-containing 20 (ZBTB20), a member of BTB/POZ family, functions in neurogenesis and represses α-fetoprotein gene transcription in liver. However, the immunological functions of ZBTB20 remain unknown. Here, we found that myeloid cell-specific ZBTB20 KO mice were resistant to endotoxin shock and Escherichia coli-caused sepsis. ZBTB20 deficiency attenuated TLR-triggered production of proinflammatory cytokines and type I IFN in macrophages, which attributed to higher abundance of IκBα protein and impaired activity of NF-κB. Furthermore, ChIP and next generation high-throughput DNA sequencing assay showed that ZBTB20 specifically bound to IκBα gene promoter (+1 to +60 region) after TLR activation. ZBTB20 could inhibit IκBα gene transcription, govern IκBα protein expression, and then promote NF-κB activation. Therefore, transcriptional repressor ZBTB20 is needed to promote full activation of TLR signaling and TLR-triggered innate immune response by selectively suppressing the suppressor IκBα gene transcription.
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50
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Nielsen JV, Thomassen M, Møllgård K, Noraberg J, Jensen NA. Zbtb20 defines a hippocampal neuronal identity through direct repression of genes that control projection neuron development in the isocortex. ACTA ACUST UNITED AC 2013; 24:1216-29. [PMID: 23283686 DOI: 10.1093/cercor/bhs400] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hippocampal pyramidal neurons are important for encoding and retrieval of spatial maps and episodic memories. While previous work has shown that Zbtb20 is a cell fate determinant for CA1 pyramidal neurons, the regulatory mechanisms governing this process are not known. In this study, we demonstrate that Zbtb20 binds to genes that control neuronal subtype specification in the developing isocortex, including Cux1, Cux2, Fezf2, Foxp2, Mef2c, Rorb, Satb2, Sox5, Tbr1, Tle4, and Zfpm2. We show that Zbtb20 represses these genes during ectopic CA1 pyramidal neuron development in transgenic mice. These data reveal a novel regulatory mechanism by which Zbtb20 suppresses the acquisition of an isocortical fate during archicortical neurogenesis to ensure commitment to a CA1 pyramidal neuron fate. We further show that the expression pattern of Zbtb20 is evolutionary conserved in the fetal human hippocampus, where it is complementary to the expression pattern of the Zbtb20 target gene Tbr1. Therefore, the disclosed Zbtb20-mediated transcriptional repressor mechanism may be involved in development of the human archicortex.
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Affiliation(s)
- Jakob V Nielsen
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, DK-5000 Odense C, Denmark
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