|
1
|
Meng C, Lin K, Shi W, Teng H, Wan X, DeBruine A, Wang Y, Liang X, Leo J, Chen F, Gu Q, Zhang J, Van V, Maldonado KL, Gan B, Ma L, Lu Y, Zhao D. Histone methyltransferase ASH1L primes metastases and metabolic reprogramming of macrophages in the bone niche. Nat Commun 2025; 16:4681. [PMID: 40394007 PMCID: PMC12092585 DOI: 10.1038/s41467-025-59381-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 04/22/2025] [Indexed: 05/22/2025] Open
Abstract
Bone metastasis is a major cause of cancer death; however, the epigenetic determinants driving this process remain elusive. Here, we report that histone methyltransferase ASH1L is genetically amplified and is required for bone metastasis in men with prostate cancer. ASH1L rewires histone methylations and cooperates with HIF-1α to induce pro-metastatic transcriptome in invading cancer cells, resulting in monocyte differentiation into lipid-associated macrophage (LA-TAM) and enhancing their pro-tumoral phenotype in the metastatic bone niche. We identified IGF-2 as a direct target of ASH1L/HIF-1α and mediates LA-TAMs' differentiation and phenotypic changes by reprogramming oxidative phosphorylation. Pharmacologic inhibition of the ASH1L-HIF-1α-macrophages axis elicits robust anti-metastasis responses in preclinical models. Our study demonstrates epigenetic alterations in cancer cells reprogram metabolism and features of myeloid components, facilitating metastatic outgrowth. It establishes ASH1L as an epigenetic driver priming metastasis and macrophage plasticity in the bone niche, providing a bona fide therapeutic target in metastatic malignancies.
Collapse
Affiliation(s)
- Chenling Meng
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Kevin Lin
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Wei Shi
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Hongqi Teng
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Xinhai Wan
- Department of Endocrine Neoplasia & Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Anna DeBruine
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Yin Wang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Xin Liang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Javier Leo
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Feiyu Chen
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Qianlin Gu
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Jie Zhang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Vivien Van
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Kiersten L Maldonado
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Boyi Gan
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Li Ma
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Yue Lu
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| | - Di Zhao
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| |
Collapse
|
|
2
|
Mendoza-Castrejon J, Yang W, Denby E, Wang H, Casey EB, Muthukumar R, Patel RM, Yoon J, Li Y, White JM, Chen R, Batista LFZ, Magee JA. Fetal context conveys heritable protection against MLL-rearranged leukemia that depends on MLL3. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.11.642680. [PMID: 40161712 PMCID: PMC11952435 DOI: 10.1101/2025.03.11.642680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
MLL rearrangements ( MLL r) are the most common cause of congenital and infant leukemias. MLL r arise prior to birth and require few cooperating mutations for transformation, yet congenital leukemias are 10-fold less common than infant leukemias and >100-fold less common than childhood leukemias overall. This raises the question of whether mechanisms exist to suppress leukemic transformation during fetal life, thereby protecting the developing fetus from malignancy during a period of rapid hematopoietic progenitor expansion. Here, we use mouse models to show that fetal MLL::ENL exposure creates a heritable, leukemia-resistant state. MLL::ENL imposes a negative selective pressure on fetal hematopoietic progenitors. It leads to postnatal loss of self-renewal gene expression and enhanced myeloid differentiation that precludes transformation. These changes do not occur when MLL::ENL is induced shortly after birth, and transformation proceeds efficiently in this context. The fetal barrier to transformation is enforced by the histone methyltransferase MLL3. It can be overcome by cooperating mutations, such as Nras G12D , or through somatic or germline inactivation of MLL3. Heritable fetal protection against leukemic transformation may explain the low incidence of congenital leukemias in humans despite prenatal MLL rearrangement.
Collapse
|
|
3
|
Vann KR, Sharma R, Hsu CC, Devoucoux M, Tencer AH, Zeng L, Lin K, Zhu L, Li Q, Lachance C, Ospina RR, Tong Q, Cheung KL, Yang S, Biswas S, Xuan H, Gatchalian J, Alamillo L, Wang J, Jang SM, Klein BJ, Lu Y, Ernst P, Strahl BD, Rothbart SB, Walsh MJ, Cleary ML, Côté J, Shi X, Zhou MM, Kutateladze TG. Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation. Nat Commun 2025; 16:2235. [PMID: 40044670 PMCID: PMC11883000 DOI: 10.1038/s41467-025-57556-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 02/20/2025] [Indexed: 03/09/2025] Open
Abstract
The histone H3K36-specific methyltransferase ASH1L plays a critical role in development and is frequently dysregulated in human diseases, particularly cancer. Here, we report on the biological functions of the C-terminal region of ASH1L encompassing a bromodomain (ASH1LBD), a plant homeodomain (ASH1LPHD) finger, and a bromo-adjacent homology (ASH1LBAH) domain, structurally characterize these domains, describe their mechanisms of action, and explore functional crosstalk between them. We find that ASH1LPHD recognizes H3K4me2/3, whereas the neighboring ASH1LBD and ASH1LBAH have DNA binding activities. The DNA binding function of ASH1LBAH is a driving force for the association of ASH1L with the linker DNA in the nucleosome, and the large interface with ASH1LPHD stabilizes the ASH1LBAH fold, merging two domains into a single module. We show that ASH1L is involved in embryonic stem cell differentiation and co-localizes with H3K4me3 but not with H3K36me2 at transcription start sites of target genes and genome wide, and that the interaction of ASH1LPHD with H3K4me3 is inhibitory to the H3K36me2-specific catalytic activity of ASH1L. Our findings shed light on the mechanistic details by which the C-terminal domains of ASH1L associate with chromatin and regulate the enzymatic function of ASH1L.
Collapse
Affiliation(s)
- Kendra R Vann
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Rajal Sharma
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Chih-Chao Hsu
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Maeva Devoucoux
- St-Patrick Research Group in Basic Oncology, Oncology Division of CHU de Québec-Université Laval Research, Laval University Cancer Research Center, Quebec City, Québec, G1R 3S3, Canada
| | - Adam H Tencer
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Lei Zeng
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Kevin Lin
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Li Zhu
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Qin Li
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
| | - Catherine Lachance
- St-Patrick Research Group in Basic Oncology, Oncology Division of CHU de Québec-Université Laval Research, Laval University Cancer Research Center, Quebec City, Québec, G1R 3S3, Canada
| | - Ruben Rosas Ospina
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Qiong Tong
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Ka Lung Cheung
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Shuai Yang
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Soumi Biswas
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Hongwen Xuan
- Department of Epigenetics, Van Andel Research Institute, Grand Rapids, MI, 49503, USA
| | - Jovylyn Gatchalian
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Lorena Alamillo
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Jianlong Wang
- Department of Medicine, Columbia Center for Human Development, Columbia University Irving Medical Center, New York, NY, 10032, USA
| | - Suk Min Jang
- St-Patrick Research Group in Basic Oncology, Oncology Division of CHU de Québec-Université Laval Research, Laval University Cancer Research Center, Quebec City, Québec, G1R 3S3, Canada
| | - Brianna J Klein
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Yue Lu
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Patricia Ernst
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Brian D Strahl
- Department of Biochemistry & Biophysics, The University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA
| | - Scott B Rothbart
- Department of Epigenetics, Van Andel Research Institute, Grand Rapids, MI, 49503, USA
- Department of Biochemistry & Biophysics, The University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA
| | - Martin J Walsh
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Michael L Cleary
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Jacques Côté
- St-Patrick Research Group in Basic Oncology, Oncology Division of CHU de Québec-Université Laval Research, Laval University Cancer Research Center, Quebec City, Québec, G1R 3S3, Canada
| | - Xiaobing Shi
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- Department of Epigenetics, Van Andel Research Institute, Grand Rapids, MI, 49503, USA
| | - Ming-Ming Zhou
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
| | - Tatiana G Kutateladze
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
| |
Collapse
|
|
4
|
Liao B, Xie W, He S. Novel heterozygous ASH1L nonsense variant involved in mild intellectual disability. Front Neurol 2025; 16:1524532. [PMID: 39902220 PMCID: PMC11788156 DOI: 10.3389/fneur.2025.1524532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 01/06/2025] [Indexed: 02/05/2025] Open
Abstract
Mutations in ASH1L have been associated with a range of phenotypes, including intellectual disability (ID), autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), seizures, as well as differences in skeletal, muscular, and sleep functions. In this study, we describe a patient diagnosed with mild ID, and whole-exome sequencing (WES) of the family identified a novel heterozygous nonsense variant, NM_018489.2: c.2479A > T (p.Lys827*), located in exon 3 of ASH1L, which was predicted to be pathogenic. The nonsense variant in the mild ID patient may disrupt ASH1L function by destabilizing its spatial conformation, leading to decreased activity of the catalytic H3K36 methylation, thereby affecting neurological function. A review of reported ASH1L nonsense mutations to explore genotype-phenotype correlations suggested that these variants typically result in a loss of function. Our findings contribute to understanding the neurodevelopmental pathogenesis of mild ID in patients with the ASH1L nonsense variant mutation.
Collapse
Affiliation(s)
- Baoqiong Liao
- Ganzhou Maternal and Child Health Hospital, Ganzhou, Jiangxi, China
- Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fuzhou, Fujian, China
| | - Wuming Xie
- Ganzhou Peoples Hospital, Ganzhou, Jiangxi, China
| | - Shuwen He
- Department of Chemistry and Molecular Biology, Gothenburg University, Gothenburg, Sweden
| |
Collapse
|
|
5
|
Huang G, Stevens R, Hucek D, Purohit T, Li S, Miao H, Trost E, Hewett G, Clegg B, Park S, Rajanayake KK, Wen B, Sun D, Cierpicki T, Grembecka J. Structure-Based Development of Novel Spiro-Piperidine ASH1L Inhibitors. J Med Chem 2025; 68:174-195. [PMID: 39680643 PMCID: PMC12013431 DOI: 10.1021/acs.jmedchem.4c01673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2024]
Abstract
The absent, small, or homeotic-like 1 (ASH1L) protein is a histone lysine methyltransferase that plays a crucial role in various cancers, including leukemia. Despite representing an attractive therapeutic target, only one class of ASH1L inhibitors was identified to date. Herein, we report development of advanced ASH1L inhibitors targeting the catalytic SET domain, which were designed to access previously unexplored binding pocket on ASH1L. Extensive medicinal chemistry combined with structure-based design led to identification of 66s (AS-254s), a highly potent and selective ASH1L inhibitor (IC50 = 94 nM), representing substantially improved inhibitory activity over previously reported compounds targeting ASH1L. Furthermore, 66s effectively blocked cell proliferation and induced apoptosis and differentiation in leukemia cells harboring MLL1 translocations. Overall, this work provides a high-quality chemical probe targeting the catalytic SET domain of ASH1L with increased inhibitory activity and cellular efficacy to study biological functions of ASH1L and potentially to develop novel anticancer therapeutics.
Collapse
Affiliation(s)
- Guang Huang
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Rhiannon Stevens
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Devon Hucek
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Trupta Purohit
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Shuangjiang Li
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Hongzhi Miao
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Elise Trost
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Geoff Hewett
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Bradley Clegg
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - SeRa Park
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | | | - Bo Wen
- College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Duxin Sun
- College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Tomasz Cierpicki
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jolanta Grembecka
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| |
Collapse
|
|
6
|
Yu XH, Xie Y, Yu J, Zhang KN, Guo ZB, Wang D, Li ZX, Zhang WQ, Tan YY, Zhang L, Jiang WT. Loss-of-function mutations of microRNA-142-3p promote ASH1L expression to induce immune evasion and hepatocellular carcinoma progression. World J Gastroenterol 2025; 31:101198. [PMID: 39777247 PMCID: PMC11684187 DOI: 10.3748/wjg.v31.i1.101198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 09/28/2024] [Accepted: 11/14/2024] [Indexed: 12/09/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) has been a pervasive malignancy throughout the world with elevated mortality. Efficient therapeutic targets are beneficial to treat and predict the disease. Currently, the exact molecular mechanisms leading to the progression of HCC are still unclear. Research has shown that the microRNA-142-3p level decreases in HCC, whereas bioinformatics analysis of the cancer genome atlas database shows the ASH1L expression increased among liver tumor tissues. In this paper, we will explore the effects and mechanisms of microRNA-142-3p and ASH1L affect the prognosis of HCC patients and HCC cell bioactivity, and the association between them. AIM To investigate the effects and mechanisms of microRNA-142-3p and ASH1L on the HCC cell bioactivity and prognosis of HCC patients. METHODS In this study, we grouped HCC patients according to their immunohistochemistry results of ASH1L with pathological tissues, and retrospectively analyzed the prognosis of HCC patients. Furthermore, explored the roles and mechanisms of microRNA-142-3p and ASH1L by cellular and animal experiments, which involved the following experimental methods: Immunohistochemical staining, western blot, quantitative real-time-polymerase chain reaction, flow cytometric analysis, tumor xenografts in nude mice, etc. The statistical methods involved in this study contained t-test, one-way analysis of variance, the χ 2 test, the Kaplan-Meier approach and the log-rank test. RESULTS In this study, we found that HCC patients with high expression of ASH1L possess a more recurrence rate as well as a decreased overall survival rate. ASH1L promotes the tumorigenicity of HCC and microRNA-142-3p exhibits reduced expression in HCC tissues and interacts with ASH1L through targeting the ASH1L 3'untranslated region. Furthermore, microRNA-142-3p promotes apoptosis and inhibits proliferation, invasion, and migration of HCC cell lines in vitro via ASH1L. For the exploration mechanism, we found ASH1L may promote an immunosuppressive microenvironment in HCC and ASH1L affects the expression of the cell junction protein zonula occludens-1, which is potentially relevant to the immune system. CONCLUSION Loss function of microRNA-142-3p induces cancer progression and immune evasion through upregulation of ASH1L in HCC. Both microRNA-142-3p and ASH1L can feature as new biomarker for HCC in the future.
Collapse
Affiliation(s)
- Xing-Hui Yu
- School of Medicine, Nankai University, Tianjin 300192, China
- Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin First Center Hospital, Tianjin 300192, China
| | - Yan Xie
- Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin First Center Hospital, Tianjin 300192, China
- Department of Liver Transplantation, Tianjin First Center Hospital, Tianjin 300192, China
| | - Jian Yu
- First Central Clinical School, Tianjin Medical University, Tianjin 300192, China
| | - Kun-Ning Zhang
- School of Medicine, Nankai University, Tianjin 300192, China
| | - Zhou-Bo Guo
- First Central Clinical School, Tianjin Medical University, Tianjin 300192, China
| | - Di Wang
- First Central Clinical School, Tianjin Medical University, Tianjin 300192, China
| | - Zhao-Xian Li
- School of Medicine, Nankai University, Tianjin 300192, China
| | - Wei-Qi Zhang
- School of Medicine, Nankai University, Tianjin 300192, China
| | - Yu-Ying Tan
- Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin First Center Hospital, Tianjin 300192, China
| | - Li Zhang
- Department of Liver Transplantation, Tianjin First Center Hospital, Tianjin 300192, China
| | - Wen-Tao Jiang
- School of Medicine, Nankai University, Tianjin 300192, China
- Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin First Center Hospital, Tianjin 300192, China
- Department of Liver Transplantation, Tianjin First Center Hospital, Tianjin 300192, China
| |
Collapse
|
|
7
|
Zhang J, Sun Q, Liu L, Yang S, Zhang X, Miao YL, Liu X. Histone methyltransferases MLL2 and SETD1A/B play distinct roles in H3K4me3 deposition during the transition from totipotency to pluripotency. EMBO J 2025; 44:437-456. [PMID: 39639179 PMCID: PMC11730331 DOI: 10.1038/s44318-024-00329-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 11/11/2024] [Accepted: 11/19/2024] [Indexed: 12/07/2024] Open
Abstract
In early mammalian embryogenesis, a shift from non-canonical histone H3 lysine 4 trimethylation (H3K4me3) linked to transcriptional repression to canonical H3K4me3 indicating active promoters occurs during zygotic genome activation (ZGA). However, the mechanisms and roles of these H3K4me3 states in embryogenesis remain poorly understood. Our research reveals that the histone methyltransferase MLL2 is responsible for installing H3K4me3 (both non-canonical and canonical) in totipotent embryos, while a transition to SETD1A/B-deposited H3K4me3 occurs in pluripotent embryos. Interestingly, MLL2-mediated H3K4me3 operates independently of transcription, fostering a relaxed chromatin state conducive to totipotency rather than directly influencing transcription. Conversely, SETD1A/B-mediated H3K4me3, which depends on transcription, is crucial for facilitating expression of genes essential for pluripotency and pre-implantation development. Our findings highlight the role of the H3K4me3 transition, mediated by an MLL2-to-SETD1A/B relay mechanism, in the regulation of transition from totipotency to pluripotency during early embryogenesis.
Collapse
Affiliation(s)
- Jingjing Zhang
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, China
| | - Qiaoran Sun
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, China
| | - Liang Liu
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, China
| | - Shichun Yang
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, China
| | - Xia Zhang
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, China
| | - Yi-Liang Miao
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, China.
- Hubei Hongshan Laboratory, Wuhan, China.
- Frontiers Science Center for Animal Breeding and Sustainable Production, Huazhong Agricultural University, Ministry of Education, Wuhan, China.
| | - Xin Liu
- Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, China.
| |
Collapse
|
|
8
|
Jhanji M, Ward JA, Leung CS, Krall CL, Ritchie FD, Guevara A, Vestergaard K, Yoon B, Amin K, Berto S, Liu J, Lizarraga SB. Dynamic Regulation OF The Chromatin Environment By Ash1L Modulates Human Neuronal Structure And Function. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.02.625500. [PMID: 39677608 PMCID: PMC11642754 DOI: 10.1101/2024.12.02.625500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Precise regulation of the chromatin environment through post-translational histone modification modulates transcription and controls brain development. Not surprisingly, mutations in a large number of histone-modifying enzymes underlie complex brain disorders. In particular, the histone methyltransferase ASH1L modifies histone marks linked to transcriptional activation and has been implicated in multiple neuropsychiatric disorders. However, the mechanisms underlying the pathobiology of ASH1L-asociated disease remain underexplored. We generated human isogenic stem cells with a mutation in ASH1L's catalytic domain. We find that ASH1L dysfunction results in reduced neurite outgrowth, which correlates with alterations in the chromatin profile of activating and repressive histone marks, as well as the dysregulation of gene programs important for neuronal structure and function implicated in neuropsychiatric disease. We also identified a novel regulatory node implicating both the SP and Krüppel -like families of transcription factors and ASH1L relevant to human neuronal development. Finally, we rescue cellular defects linked to ASH1L dysfunction by leveraging two independent epigenetic mechanisms that promote transcriptional activation. In summary, we identified an ASH1L-driven epigenetic and transcriptional axis essential for human brain development and complex brain disorders that provide insights into future therapeutic strategies for ASH1L-related disorders.
Collapse
|
|
9
|
Du Y, Wu S, Xi S, Xu W, Sun L, Yan J, Gao H, Wang Y, Zheng J, Wang F, Yang H, Xie D, Chen X, Ou X, Guan X, Li Y. ASH1L in Hepatoma Cells and Hepatic Stellate Cells Promotes Fibrosis-Associated Hepatocellular Carcinoma by Modulating Tumor-Associated Macrophages. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2404756. [PMID: 39377228 PMCID: PMC11615825 DOI: 10.1002/advs.202404756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 09/06/2024] [Indexed: 10/09/2024]
Abstract
Hepatocellular carcinoma (HCC) often occurs in the context of fibrosis or cirrhosis. Methylation of histone is an important epigenetic mechanism, but it is unclear whether histone methyltransferases are potent targets for fibrosis-associated HCC therapy. ASH1L, an H3K4 methyltransferase, is found at higher levels in activated hepatic stellate cells (HSCs) and hepatoma cells. To determine the role of ASH1L in vivo, transgenic mice with conditional Ash1l depletion in the hepatocyte cell lineage (Ash1lflox/floxAlbcre) or HSCs (Ash1lflox/floxGFAPcreERT2) are generated, and these mice are challenged in a diethylnitrosamine (DEN)/carbon tetrachloride (CCl4)-induced model of liver fibrosis and HCC. Depleting Ash1l in both hepatocytes and HSCs mitigates hepatic fibrosis and HCC development. Multicolor flow cytometry, bulk, and single-cell transcriptomic sequencing reveal that ASH1L creates an immunosuppressive microenvironment. Mechanically, ASH1L-mediated H3K4me3 modification increases the expression of CCL2 and CSF1, which recruites and polarizes M2-like pro-tumorigenic macrophages. The M2-like macrophages further enhance tumor cell proliferation and suppress CD8+ T cell activation. AS-99, a small molecule inhibitor of ASH1L, demonstrates similar anti-fibrosis and tumor-suppressive effects. Of pathophysiological significance, the increased expression levels of mesenchymal ASH1L and M2 marker CD68 are associated with poor prognosis of HCC. The findings reveal ASH1L as a potential small-molecule therapeutic target against fibrosis-related HCC.
Collapse
Affiliation(s)
- Yuyang Du
- Department of Systems Biology, School of Life Sciences, Southern University of Science and TechnologyShenzhen518055China
| | - Shasha Wu
- Department of Systems Biology, School of Life Sciences, Southern University of Science and TechnologyShenzhen518055China
| | - Shaoyan Xi
- Department of PathologySun Yat‐Sen University Cancer CenterGuangzhou510275China
| | - Wei Xu
- GMU‐GIBH Joint School of Life Sciences, The Guangdong‐Hong Kong‐Macau Joint Laboratory for Cell Fate Regulation and DiseasesGuangzhou Medical UniversityGuangzhou511436China
| | - Liangzhan Sun
- Department of Systems Biology, School of Life Sciences, Southern University of Science and TechnologyShenzhen518055China
- Department of Clinical OncologyThe University of Hong KongHong Kong999077China
- Institute of Cancer ResearchShenzhen Bay LaboratoryShenzhen518067China
| | - Jingsong Yan
- Department of Systems Biology, School of Life Sciences, Southern University of Science and TechnologyShenzhen518055China
| | - Han Gao
- Department of Systems Biology, School of Life Sciences, Southern University of Science and TechnologyShenzhen518055China
| | - Yanchen Wang
- Shenzhen HospitalSouthern Medical UniversityShenzhen518000China
| | - Jingyi Zheng
- Shenzhen HospitalSouthern Medical UniversityShenzhen518000China
| | - Fenfen Wang
- Department of Systems Biology, School of Life Sciences, Southern University of Science and TechnologyShenzhen518055China
| | - Hui Yang
- Department of Systems Biology, School of Life Sciences, Southern University of Science and TechnologyShenzhen518055China
| | - Dan Xie
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510080China
| | - Xi Chen
- Department of Systems Biology, School of Life Sciences, Southern University of Science and TechnologyShenzhen518055China
| | - Xijun Ou
- School of Life SciencesSouthern University of Science and TechnologyShenzhen518055China
| | - Xin‐Yuan Guan
- Department of Clinical OncologyThe University of Hong KongHong Kong999077China
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510080China
- The University of Hong Kong‐Shenzhen HospitalShenzhen518053China
| | - Yan Li
- Shenzhen HospitalSouthern Medical UniversityShenzhen518000China
| |
Collapse
|
|
10
|
Ortiz-Hernandez GL, Sanchez-Hernandez ES, Ochoa PT, Casiano CA. The Emerging Roles of the Stress Epigenetic Reader LEDGF/p75 in Cancer Biology and Therapy Resistance: Mechanisms and Targeting Opportunities. Cancers (Basel) 2024; 16:3957. [PMID: 39682146 DOI: 10.3390/cancers16233957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/19/2024] [Accepted: 11/21/2024] [Indexed: 12/18/2024] Open
Abstract
The lens epithelium derived growth factor of 75 kD (LEDGF/p75) is a transcription co-activator and epigenetic reader that has emerged as a stress oncoprotein in multiple human cancers. Growing evidence indicates that it promotes tumor cell survival against certain therapeutic drugs. The amino (N)-terminal region of LEDGF/p75 contains a PWWP domain that reads methylated histone marks, critical for recognizing transcriptionally active chromatin sites. Its carboxyl (C)-terminus has an integrase binding domain (IBD) that serves as the binding site for the HIV-1 integrase and multiple oncogenic transcription factors. Acting as hubs for protein-protein interactions, both domains facilitate the tethering of oncogenic transcription factors and regulators to active chromatin to regulate mRNA splicing, promote DNA repair, and enhance the expression of stress and cancer-related genes that contribute to tumor cell aggressiveness and chemoresistance. This review summarizes our current knowledge of the emerging roles of LEDGF/p75 in cancer biology and therapy resistance and discusses its potential as a novel oncotherapeutic target in combinatorial treatments.
Collapse
Affiliation(s)
- Greisha L Ortiz-Hernandez
- Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
| | - Evelyn S Sanchez-Hernandez
- Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
| | - Pedro T Ochoa
- Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
| | - Carlos A Casiano
- Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
- Department of Medicine, Division of Rheumatology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
- Cancer Center, Loma Linda University Health, Loma Linda, CA 92350, USA
| |
Collapse
|
|
11
|
Huang G, Cierpicki T, Grembecka J. Thioamides in medicinal chemistry and as small molecule therapeutic agents. Eur J Med Chem 2024; 277:116732. [PMID: 39106658 PMCID: PMC12009601 DOI: 10.1016/j.ejmech.2024.116732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/18/2024] [Accepted: 07/30/2024] [Indexed: 08/09/2024]
Abstract
Thioamides, which are fascinating isosteres of amides, have garnered significant attention in drug discovery and medicinal chemistry programs, spanning peptides and small molecule compounds. This review provides an overview of the various applications of thioamides in small molecule therapeutic agents targeting a range of human diseases, including cancer, microbial infections (e.g., tuberculosis, bacteria, and fungi), viral infections, neurodegenerative conditions, analgesia, and others. Particular focus is given to design strategies of biologically active thioamide-containing compounds and their biological targets, such as kinases and histone methyltransferase ASH1L. Additionally, the review discusses the impact of the thioamide moiety on key properties, including potency, target interactions, physicochemical characteristics, and pharmacokinetics profiles. We hope that this work will offer valuable insights to inspire the future development of novel bioactive thioamide-containing compounds, facilitating their effective use in combating a wide array of human diseases.
Collapse
Affiliation(s)
- Guang Huang
- Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
| | - Tomasz Cierpicki
- Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Jolanta Grembecka
- Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA
| |
Collapse
|
|
12
|
Demoen L, Matthijssens F, Reunes L, Palhais B, Lintermans B, T’Sas S, Fijalkowski I, Taminau J, Akele MZ, Van Belle S, Taghon T, Deforce D, Van Nieuwerburgh F, Berx G, Ntziachristos P, Debyser Z, Durinck K, Pieters T, Goossens S, Van Vlierberghe P. A dual role for PSIP1/LEDGF in T cell acute lymphoblastic leukemia. SCIENCE ADVANCES 2024; 10:eado6765. [PMID: 39485844 PMCID: PMC11529709 DOI: 10.1126/sciadv.ado6765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 09/30/2024] [Indexed: 11/03/2024]
Abstract
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Current intensified therapeutic protocols coincide with severe side effects, and no salvage therapy is available for primary therapy-resistant or relapsed patients. This highlights the need to identify new therapeutic targets in T-ALL. PSIP1, dispensable for normal hematopoiesis, is a dependency factor in KMT2A-rearranged myeloid leukemia. Nonetheless, loss-of-function mutations suggest a tumor suppressor role for PSIP1 in T-ALL. Here, we demonstrate that the loss of Psip1 accelerates T-ALL initiation in mice which we correlated with reduced H3K27me3 binding. Contrastingly, loss of PSIP1 impaired cell proliferation in several T-ALL cell lines. In cell lines, PSIP1 down-regulation leads to a reduction of COX20, an assembly factor of the cytochrome c oxidase in the mitochondria, and to a reduction in mitochondrial respiration. This indicates that PSIP1 can exert a dual role in the context of T-ALL, either as a tumor suppressor gene during tumor initiation or as a dependency factor in tumor maintenance.
Collapse
Affiliation(s)
- Lisa Demoen
- Lab of Normal and Malignant Hematopoiesis, Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000 Ghent, Belgium
| | - Filip Matthijssens
- Lab of Normal and Malignant Hematopoiesis, Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000 Ghent, Belgium
| | - Lindy Reunes
- Lab of Normal and Malignant Hematopoiesis, Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000 Ghent, Belgium
| | - Bruno Palhais
- Lab of Normal and Malignant Hematopoiesis, Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000 Ghent, Belgium
| | - Béatrice Lintermans
- Lab of Normal and Malignant Hematopoiesis, Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000 Ghent, Belgium
| | - Sara T’Sas
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000 Ghent, Belgium
- Unit for Translational Research in Oncology, Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium
| | - Igor Fijalkowski
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000 Ghent, Belgium
- Leukemia Therapy Resistance Laboratory, Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
| | - Joachim Taminau
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000 Ghent, Belgium
- Department Biomedical Molecular Biology, 9000 Ghent University, Ghent, Belgium
| | - Muluembet Z. Akele
- Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit (KU) Leuven, 3000 Leuven, Belgium
| | - Siska Van Belle
- Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit (KU) Leuven, 3000 Leuven, Belgium
| | - Tom Taghon
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000 Ghent, Belgium
- T Cell Team Taghon, Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium
| | - Dieter Deforce
- Laboratory of Pharmaceutical Biotechnology, Ghent University, 9000 Ghent, Belgium
| | | | - Geert Berx
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000 Ghent, Belgium
- Department Biomedical Molecular Biology, 9000 Ghent University, Ghent, Belgium
| | - Panagiotis Ntziachristos
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000 Ghent, Belgium
- Leukemia Therapy Resistance Laboratory, Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
| | - Zeger Debyser
- Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit (KU) Leuven, 3000 Leuven, Belgium
| | - Kaat Durinck
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000 Ghent, Belgium
- Pediatric Precision Oncology Lab, Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
| | - Tim Pieters
- Lab of Normal and Malignant Hematopoiesis, Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000 Ghent, Belgium
- Unit for Translational Research in Oncology, Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium
- Leukemia Therapy Resistance Laboratory, Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
| | - Steven Goossens
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000 Ghent, Belgium
- Unit for Translational Research in Oncology, Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium
| | - Pieter Van Vlierberghe
- Lab of Normal and Malignant Hematopoiesis, Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000 Ghent, Belgium
| |
Collapse
|
|
13
|
Shipman GA, Padilla R, Horth C, Hu B, Bareke E, Vitorino FN, Gongora JM, Garcia BA, Lu C, Majewski J. Systematic perturbations of SETD2, NSD1, NSD2, NSD3, and ASH1L reveal their distinct contributions to H3K36 methylation. Genome Biol 2024; 25:263. [PMID: 39390582 PMCID: PMC11465688 DOI: 10.1186/s13059-024-03415-3] [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: 09/22/2023] [Accepted: 10/01/2024] [Indexed: 10/12/2024] Open
Abstract
BACKGROUND Methylation of histone 3 lysine 36 (H3K36me) has emerged as an essential epigenetic component for the faithful regulation of gene expression. Despite its importance in development and disease, how the molecular agents collectively shape the H3K36me landscape is unclear. RESULTS We use mouse mesenchymal stem cells to perturb the H3K36me methyltransferases (K36MTs) and infer the activities of the five most prominent enzymes: SETD2, NSD1, NSD2, NSD3, and ASH1L. We find that H3K36me2 is the most abundant of the three methylation states and is predominantly deposited at intergenic regions by NSD1, and partly by NSD2. In contrast, H3K36me1/3 are most abundant within exons and are positively correlated with gene expression. We demonstrate that while SETD2 deposits most H3K36me3, it may also deposit H3K36me2 within transcribed genes. Additionally, loss of SETD2 results in an increase of exonic H3K36me1, suggesting other (K36MTs) prime gene bodies with lower methylation states ahead of transcription. While NSD1/2 establish broad intergenic H3K36me2 domains, NSD3 deposits H3K36me2 peaks on active promoters and enhancers. Meanwhile, the activity of ASH1L is restricted to the regulatory elements of developmentally relevant genes, and our analyses implicate PBX2 as a potential recruitment factor. CONCLUSIONS Within genes, SETD2 primarily deposits H3K36me3, while the other K36MTs deposit H3K36me1/2 independently of SETD2 activity. For the deposition of H3K36me1/2, we find a hierarchy of K36MT activities where NSD1 > NSD2 > NSD3 > ASH1L. While NSD1 and NSD2 are responsible for most genome-wide propagation of H3K36me2, the activities of NSD3 and ASH1L are confined to active regulatory elements.
Collapse
Affiliation(s)
- Gerry A Shipman
- Department of Human Genetics, McGill University, Montreal, QC, H3A 1B1, Canada
- McGill University Genome Centre, Montreal, QC, H3A 0G1, Canada
| | - Reinnier Padilla
- Department of Human Genetics, McGill University, Montreal, QC, H3A 1B1, Canada
- McGill University Genome Centre, Montreal, QC, H3A 0G1, Canada
| | - Cynthia Horth
- Department of Human Genetics, McGill University, Montreal, QC, H3A 1B1, Canada
- McGill University Genome Centre, Montreal, QC, H3A 0G1, Canada
| | - Bo Hu
- Department of Human Genetics, McGill University, Montreal, QC, H3A 1B1, Canada
- McGill University Genome Centre, Montreal, QC, H3A 0G1, Canada
| | - Eric Bareke
- Department of Human Genetics, McGill University, Montreal, QC, H3A 1B1, Canada
- McGill University Genome Centre, Montreal, QC, H3A 0G1, Canada
| | - Francisca N Vitorino
- Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Joanna M Gongora
- Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Benjamin A Garcia
- Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Chao Lu
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, 10032, USA
| | - Jacek Majewski
- Department of Human Genetics, McGill University, Montreal, QC, H3A 1B1, Canada.
- McGill University Genome Centre, Montreal, QC, H3A 0G1, Canada.
| |
Collapse
|
|
14
|
Yancoskie M, Khaleghi R, Gururajan A, Raghunathan A, Gupta A, Diethelm S, Maritz C, Sturla S, Krishnan M, Naegeli H. ASH1L guards cis-regulatory elements against cyclobutane pyrimidine dimer induction. Nucleic Acids Res 2024; 52:8254-8270. [PMID: 38884271 PMCID: PMC11317172 DOI: 10.1093/nar/gkae517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 05/29/2024] [Accepted: 06/04/2024] [Indexed: 06/18/2024] Open
Abstract
The histone methyltransferase ASH1L, first discovered for its role in transcription, has been shown to accelerate the removal of ultraviolet (UV) light-induced cyclobutane pyrimidine dimers (CPDs) by nucleotide excision repair. Previous reports demonstrated that CPD excision is most efficient at transcriptional regulatory elements, including enhancers, relative to other genomic sites. Therefore, we analyzed DNA damage maps in ASH1L-proficient and ASH1L-deficient cells to understand how ASH1L controls enhancer stability. This comparison showed that ASH1L protects enhancer sequences against the induction of CPDs besides stimulating repair activity. ASH1L reduces CPD formation at C-containing but not at TT dinucleotides, and no protection occurs against pyrimidine-(6,4)-pyrimidone photoproducts or cisplatin crosslinks. The diminished CPD induction extends to gene promoters but excludes retrotransposons. This guardian role against CPDs in regulatory elements is associated with the presence of H3K4me3 and H3K27ac histone marks, which are known to interact with the PHD and BRD motifs of ASH1L, respectively. Molecular dynamics simulations identified a DNA-binding AT hook of ASH1L that alters the distance and dihedral angle between neighboring C nucleotides to disfavor dimerization. The loss of this protection results in a higher frequency of C->T transitions at enhancers of skin cancers carrying ASH1L mutations compared to ASH1L-intact counterparts.
Collapse
Affiliation(s)
- Michelle N Yancoskie
- Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich 8057, Switzerland
| | - Reihaneh Khaleghi
- Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich 8057, Switzerland
| | - Anirvinya Gururajan
- Center for Computational Natural Sciences and Bioinformatics, International Institute of Information Technology, Hyderabad 500032, India
| | - Aadarsh Raghunathan
- Center for Computational Natural Sciences and Bioinformatics, International Institute of Information Technology, Hyderabad 500032, India
| | - Aryan Gupta
- Center for Computational Natural Sciences and Bioinformatics, International Institute of Information Technology, Hyderabad 500032, India
| | - Sarah Diethelm
- Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich 8057, Switzerland
| | - Corina Maritz
- Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich 8057, Switzerland
| | - Shana J Sturla
- Department of Health Sciences and Technology, ETH Zurich, Zurich 8092, Switzerland
| | - Marimuthu Krishnan
- Center for Computational Natural Sciences and Bioinformatics, International Institute of Information Technology, Hyderabad 500032, India
| | - Hanspeter Naegeli
- Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich 8057, Switzerland
| |
Collapse
|
|
15
|
Mabe NW, Perry JA, Malone CF, Stegmaier K. Pharmacological targeting of the cancer epigenome. NATURE CANCER 2024; 5:844-865. [PMID: 38937652 PMCID: PMC11936478 DOI: 10.1038/s43018-024-00777-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 04/19/2024] [Indexed: 06/29/2024]
Abstract
Epigenetic dysregulation is increasingly appreciated as a hallmark of cancer, including disease initiation, maintenance and therapy resistance. As a result, there have been advances in the development and evaluation of epigenetic therapies for cancer, revealing substantial promise but also challenges. Three epigenetic inhibitor classes are approved in the USA, and many more are currently undergoing clinical investigation. In this Review, we discuss recent developments for each epigenetic drug class and their implications for therapy, as well as highlight new insights into the role of epigenetics in cancer.
Collapse
Affiliation(s)
- Nathaniel W Mabe
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Jennifer A Perry
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Clare F Malone
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Kimberly Stegmaier
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
| |
Collapse
|
|
16
|
Zhao X, Lin S, Ren H, Sun S, Zheng L, Chen LF, Wang Z. The histone methyltransferase ASH1L protects against bone loss by inhibiting osteoclastogenesis. Cell Death Differ 2024; 31:605-617. [PMID: 38431690 PMCID: PMC11094046 DOI: 10.1038/s41418-024-01274-w] [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: 08/02/2023] [Revised: 02/16/2024] [Accepted: 02/20/2024] [Indexed: 03/05/2024] Open
Abstract
Absent, small, or homeotic1-like (ASH1L) is a histone lysine methyltransferase that generally functions as a transcriptional activator in controlling cell fate. So far, its physiological relevance in bone homeostasis and osteoclast differentiation remains elusive. Here, by conditional deleting Ash1l in osteoclast progenitors of mice, we found ASH1L deficiency resulted in osteoporosis and potentiation of osteoclastogenesis in vivo and in vitro. Mechanistically, ASH1L binds the promoter of the Src homology 3 and cysteine-rich domain 2 (Stac2) and increases the gene's transcription via histone 3 lysine 4 (H3K4) trimethylation modification, thus augmenting the STAC2's protection against receptor activator of nuclear factor kB ligand (RANKL)-initiated inflammation during osteoclast formation. Collectively, we demonstrate the first piece of evidence to prove ASH1L as a critical checkpoint during osteoclastogenesis. The work sheds new light on our understanding about the biological function of ASH1L in bone homeostasis, therefore providing a valuable therapeutic target for the treatment of osteoporosis or inflammatory bone diseases.
Collapse
Affiliation(s)
- Xiaoli Zhao
- Department of Biochemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuai Lin
- Department of Biochemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Orthodontics, School and Hospital of Stomatology, Peking University, Beijing, China
| | - Hangjiang Ren
- Department of Biochemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shenghui Sun
- Department of Biochemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liyun Zheng
- Department of Biochemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lin-Feng Chen
- Department of Biochemistry, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, USA
| | - Zhen Wang
- Department of Biochemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| |
Collapse
|
|
17
|
Contreras Yametti GP, Robbins G, Chowdhury A, Narang S, Ostrow TH, Kilberg H, Greenberg J, Kramer L, Raetz E, Tsirigos A, Evensen NA, Carroll WL. SETD2 mutations do not contribute to clonal fitness in response to chemotherapy in childhood B cell acute lymphoblastic leukemia. Leuk Lymphoma 2024; 65:78-90. [PMID: 37874744 PMCID: PMC11874253 DOI: 10.1080/10428194.2023.2273752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 10/12/2023] [Accepted: 10/14/2023] [Indexed: 10/26/2023]
Abstract
Mutations in genes encoding epigenetic regulators are commonly observed at relapse in B cell acute lymphoblastic leukemia (B-ALL). Loss-of-function mutations in SETD2, an H3K36 methyltransferase, have been observed in B-ALL and other cancers. Previous studies on mutated SETD2 in solid tumors and acute myelogenous leukemia support a role in promoting resistance to DNA damaging agents. We did not observe chemoresistance, an impaired DNA damage response, nor increased mutation frequency in response to thiopurines using CRISPR-mediated knockout in wild-type B-ALL cell lines. Likewise, restoration of SETD2 in cell lines with hemizygous mutations did not increase sensitivity. SETD2 mutations affected the chromatin landscape and transcriptional output that was unique to each cell line. Collectively our data does not support a role for SETD2 mutations in driving clonal evolution and relapse in B-ALL, which is consistent with the lack of enrichment of SETD2 mutations at relapse in most studies.
Collapse
Affiliation(s)
- Gloria P. Contreras Yametti
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Perlmutter Cancer Center, NYU Langone Health, New York, NY
| | - Gabriel Robbins
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Perlmutter Cancer Center, NYU Langone Health, New York, NY
| | - Ashfiyah Chowdhury
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Perlmutter Cancer Center, NYU Langone Health, New York, NY
| | - Sonali Narang
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Perlmutter Cancer Center, NYU Langone Health, New York, NY
| | - Talia H. Ostrow
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Perlmutter Cancer Center, NYU Langone Health, New York, NY
| | - Harrison Kilberg
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Perlmutter Cancer Center, NYU Langone Health, New York, NY
| | - Joshua Greenberg
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Perlmutter Cancer Center, NYU Langone Health, New York, NY
| | - Lindsay Kramer
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Perlmutter Cancer Center, NYU Langone Health, New York, NY
| | - Elizabeth Raetz
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Perlmutter Cancer Center, NYU Langone Health, New York, NY
| | - Aristotelis Tsirigos
- Departments of Pediatrics and Pathology, Perlmutter Cancer Center, NYU Langone Health, New York, NY
| | - Nikki A. Evensen
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Perlmutter Cancer Center, NYU Langone Health, New York, NY
| | - William L. Carroll
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Perlmutter Cancer Center, NYU Langone Health, New York, NY
- Department of Pathology, NYU Langone Health, New York, NY
| |
Collapse
|
|
18
|
Juul-Dam KL, Shukla NN, Cooper TM, Cuglievan B, Heidenreich O, Kolb EA, Rasouli M, Hasle H, Zwaan CM. Therapeutic targeting in pediatric acute myeloid leukemia with aberrant HOX/MEIS1 expression. Eur J Med Genet 2023; 66:104869. [PMID: 38174649 PMCID: PMC11195042 DOI: 10.1016/j.ejmg.2023.104869] [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: 08/31/2022] [Revised: 05/21/2023] [Accepted: 10/22/2023] [Indexed: 01/05/2024]
Abstract
Despite advances in the clinical management of childhood acute myeloid leukemia (AML) during the last decades, outcome remains fatal in approximately one third of patients. Primary chemoresistance, relapse and acute and long-term toxicities to conventional myelosuppressive therapies still constitute significant challenges and emphasize the unmet need for effective targeted therapies. Years of scientific efforts have translated into extensive insights on the heterogeneous spectrum of genetics and oncogenic signaling pathways of AML and identified a subset of patients characterized by upregulation of HOXA and HOXB homeobox genes and myeloid ecotropic virus insertion site 1 (MEIS1). Aberrant HOXA/MEIS1 expression is associated with genotypes such as rearrangements in Histone-lysine N-methyltransferase 2A (KMT2A-r), nucleoporin 98 (NUP98-r) and mutated nucleophosmin (NPM1c) that are found in approximately one third of children with AML. AML with upregulated HOXA/MEIS1 shares a number of molecular vulnerabilities amenable to recently developed molecules targeting the assembly of protein complexes or transcriptional regulators. The interaction between the nuclear scaffold protein menin and KMT2A has gained particular interest and constitutes a molecular dependency for maintenance of the HOXA/MEIS1 transcription program. Menin inhibitors disrupt the menin-KMT2A complex in preclinical models of KMT2A-r, NUP98-r and NPM1c acute leukemias and its occupancy at target genes leading to leukemic cell differentiation and apoptosis. Early-phase clinical trials are either ongoing or in development and preliminary data suggests tolerable toxicities and encouraging efficacy of menin inhibitors in adults with relapsed or refractory KMT2A-r and NPM1c AML. The Pediatric Acute Leukemia/European Pediatric Acute Leukemia (PedAL/EUPAL) project is focused to advance and coordinate informative clinical trials with new agents and constitute an ideal framework for testing of menin inhibitors in pediatric study populations. Menin inhibitors in combination with standard chemotherapy or other targeting agents may enhance anti-leukemic effects and constitute rational treatment strategies for select genotypes of childhood AML, and provide enhanced safety to avoid differentiation syndrome. In this review, we discuss the pathophysiological mechanisms in KMT2A-r, NUP98-r and NPM1c AML, emerging molecules targeting the HOXA/MEIS1 transcription program with menin inhibitors as the most prominent examples and future therapeutic implications of these agents in childhood AML.
Collapse
Affiliation(s)
- Kristian L Juul-Dam
- Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.
| | - Neerav N Shukla
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Todd M Cooper
- Division of Hematology/Oncology, Seattle Children's Hospital, University of Washington, Seattle, WA, USA
| | - Branko Cuglievan
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Olaf Heidenreich
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - E Anders Kolb
- Division of Oncology, Nemours/Alfred I. Dupont Hospital for Children, Wilmington, DE, USA
| | - Milad Rasouli
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands
| | - Henrik Hasle
- Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - C Michel Zwaan
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands
| |
Collapse
|
|
19
|
Johannessen JA, Formica M, Haukeland ALC, Bråthen NR, Al Outa A, Aarsund M, Therrien M, Enserink JM, Knævelsrud H. The human leukemic oncogene MLL-AF4 promotes hyperplastic growth of hematopoietic tissues in Drosophila larvae. iScience 2023; 26:107726. [PMID: 37720104 PMCID: PMC10504488 DOI: 10.1016/j.isci.2023.107726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 06/25/2023] [Accepted: 08/21/2023] [Indexed: 09/19/2023] Open
Abstract
MLL-rearranged (MLL-r) leukemias are among the leukemic subtypes with poorest survival, and treatment options have barely improved over the last decades. Despite increasing molecular understanding of the mechanisms behind these hematopoietic malignancies, this knowledge has had poor translation into the clinic. Here, we report a Drosophila melanogaster model system to explore the pathways affected in MLL-r leukemia. We show that expression of the human leukemic oncogene MLL-AF4 in the Drosophila hematopoietic system resulted in increased levels of circulating hemocytes and an enlargement of the larval hematopoietic organ, the lymph gland. Strikingly, depletion of Drosophila orthologs of known interactors of MLL-AF4, such as DOT1L, rescued the leukemic phenotype. In agreement, treatment with small-molecule inhibitors of DOT1L also prevented the MLL-AF4-induced leukemia-like phenotype. Taken together, this model provides an in vivo system to unravel the genetic interactors involved in leukemogenesis and offers a system for improved biological understanding of MLL-r leukemia.
Collapse
Affiliation(s)
- Julie A. Johannessen
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Miriam Formica
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Aina Louise C. Haukeland
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Nora Rojahn Bråthen
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Amani Al Outa
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Miriam Aarsund
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Marc Therrien
- Institute for Research in Immunology and Cancer, Laboratory of Intracellular Signaling, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC H3C 3J7, Canada
- Département de pathologie et de biologie cellulaire, Université de Montréal, Montréal, QC H3C 3J7, Canada
| | - Jorrit M. Enserink
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Section for Biochemistry and Molecular Biology, The Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway
| | - Helene Knævelsrud
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| |
Collapse
|
|
20
|
Shipman GA, Padilla R, Horth C, Hu B, Bareke E, Vitorino FN, Gongora JM, Garcia BA, Lu C, Majewski J. Systematic perturbations of SETD2, NSD1, NSD2, NSD3 and ASH1L reveals their distinct contributions to H3K36 methylation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.27.559313. [PMID: 37905045 PMCID: PMC10614729 DOI: 10.1101/2023.09.27.559313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/02/2023]
Abstract
Background Methylation of histone 3 lysine 36 (H3K36me) has emerged as an essential epigenetic component for the faithful regulation of gene expression. Despite its importance in development, disease, and cancer, how the molecular agents collectively shape the H3K36me landscape is unclear. Results We use a mouse mesenchymal stem cell model to perturb the H3K36me deposition machinery and infer the activities of the five most prominent players: SETD2, NSD1, NSD2, NSD3, and ASH1L. We find that H3K36me2 is the most abundant of the three methylation states and is predominantly deposited at intergenic regions by NSD1, and partly by NSD2. In contrast, H3K36me1/3 are most abundant within exons and are positively correlated with gene expression. We demonstrate that while SETD2 deposits most H3K36me3, it also deposits H3K36me2 within transcribed genes. Additionally, loss of SETD2 results in an increase of exonic H3K36me1, suggesting other H3K36 methyltransferases (K36MTs) prime gene bodies with lower methylation states ahead of transcription. Through a reductive approach, we uncover the distribution patterns of NSD3- and ASH1L-catalyzed H3K36me2. While NSD1/2 establish broad intergenic H3K36me2 domains, NSD3 deposits H3K36me2 peaks on active promoters and enhancers. Meanwhile, the activity of ASH1L is restricted to the regulatory elements of developmentally relevant genes, and our analyses implicate PBX2 as a potential recruitment factor. Conclusions Within genes, SETD2 deposits both H3K36me2/3, while the other K36MTs are capable of depositing H3K36me1/2 independently of SETD2 activity. For the deposition of H3K36me1/2, we find a hierarchy of K36MT activities where NSD1>NSD2>NSD3>ASH1L. While NSD1 and NSD2 are responsible for most genome-wide propagation of H3K36me2, the activities of NSD3 and ASH1L are confined to active regulatory elements.
Collapse
|
|
21
|
Koutná E, Lux V, Kouba T, Škerlová J, Nováček J, Srb P, Hexnerová R, Šváchová H, Kukačka Z, Novák P, Fábry M, Poepsel S, Veverka V. Multivalency of nucleosome recognition by LEDGF. Nucleic Acids Res 2023; 51:10011-10025. [PMID: 37615563 PMCID: PMC10570030 DOI: 10.1093/nar/gkad674] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 07/01/2023] [Accepted: 08/09/2023] [Indexed: 08/25/2023] Open
Abstract
Eukaryotic transcription is dependent on specific histone modifications. Their recognition by chromatin readers triggers complex processes relying on the coordinated association of transcription regulatory factors. Although various modification states of a particular histone residue often lead to differential outcomes, it is not entirely clear how they are discriminated. Moreover, the contribution of intrinsically disordered regions outside of the specialized reader domains to nucleosome binding remains unexplored. Here, we report the structures of a PWWP domain from transcriptional coactivator LEDGF in complex with the H3K36 di- and trimethylated nucleosome, indicating that both methylation marks are recognized by PWWP in a highly conserved manner. We identify a unique secondary interaction site for the PWWP domain at the interface between the acidic patch and nucleosomal DNA that might contribute to an H3K36-methylation independent role of LEDGF. We reveal DNA interacting motifs in the intrinsically disordered region of LEDGF that discriminate between the intra- or extranucleosomal DNA but remain dynamic in the context of dinucleosomes. The interplay between the LEDGF H3K36-methylation reader and protein binding module mediated by multivalent interactions of the intrinsically disordered linker with chromatin might help direct the elongation machinery to the vicinity of RNA polymerase II, thereby facilitating productive elongation.
Collapse
Affiliation(s)
- Eliška Koutná
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague 160 00, Czech Republic
- Department of Cell Biology, Faculty of Science, Charles University, Prague 128 00, Czech Republic
| | - Vanda Lux
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague 160 00, Czech Republic
| | - Tomáš Kouba
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague 160 00, Czech Republic
| | - Jana Škerlová
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague 160 00, Czech Republic
| | | | - Pavel Srb
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague 160 00, Czech Republic
| | - Rozálie Hexnerová
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague 160 00, Czech Republic
| | - Hana Šváchová
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague 160 00, Czech Republic
| | - Zdeněk Kukačka
- Institute of Microbiology of the Czech Academy of Sciences, Prague 142 20, Czech Republic
| | - Petr Novák
- Institute of Microbiology of the Czech Academy of Sciences, Prague 142 20, Czech Republic
| | - Milan Fábry
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague 160 00, Czech Republic
| | - Simon Poepsel
- Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, Cologne 509 31, Germany
- Cologne Excellence Cluster for Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, Cologne 509 31, Germany
| | - Václav Veverka
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague 160 00, Czech Republic
- Department of Cell Biology, Faculty of Science, Charles University, Prague 128 00, Czech Republic
| |
Collapse
|
|
22
|
Al-Harthi S, Li H, Winkler A, Szczepski K, Deng J, Grembecka J, Cierpicki T, Jaremko Ł. MRG15 activates histone methyltransferase activity of ASH1L by recruiting it to the nucleosomes. Structure 2023; 31:1200-1207.e5. [PMID: 37527654 DOI: 10.1016/j.str.2023.07.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 05/16/2023] [Accepted: 07/05/2023] [Indexed: 08/03/2023]
Abstract
ASH1L is a histone methyltransferase that regulates gene expression through methylation of histone H3 on lysine K36. While the catalytic SET domain of ASH1L has low intrinsic activity, several studies found that it can be vastly enhanced by the interaction with MRG15 protein and proposed allosteric mechanism of releasing its autoinhibited conformation. Here, we found that full-length MRG15, but not the MRG domain alone, can enhance the activity of the ASH1L SET domain. In addition, we showed that catalytic activity of MRG15-ASH1L depends on nucleosome binding mediated by MRG15 chromodomain. We found that in solution MRG15 binds to ASH1L, but has no impact on the conformation of the SET domain autoinhibitory loop or the S-adenosylmethionine cofactor binding site. Moreover, MRG15 binding did not impair the potency of small molecule inhibitors of ASH1L. These findings suggest that MRG15 functions as an adapter that enhances ASH1L catalytic activity by recruiting nucleosome substrate.
Collapse
Affiliation(s)
- Samah Al-Harthi
- Smart-Health Initiative (SHI) and Red Sea Research Center (RSRC), Bioscience Program, Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia
| | - Hao Li
- Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA
| | - Alyssa Winkler
- Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA
| | - Kacper Szczepski
- Smart-Health Initiative (SHI) and Red Sea Research Center (RSRC), Bioscience Program, Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia
| | - Jing Deng
- Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA
| | - Jolanta Grembecka
- Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA
| | - Tomasz Cierpicki
- Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA.
| | - Łukasz Jaremko
- Smart-Health Initiative (SHI) and Red Sea Research Center (RSRC), Bioscience Program, Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia.
| |
Collapse
|
|
23
|
Velez J, Kaniskan HÜ, Jin J. Recent advances in developing degraders & inhibitors of lysine methyltransferases. Curr Opin Chem Biol 2023; 76:102356. [PMID: 37379717 PMCID: PMC10527319 DOI: 10.1016/j.cbpa.2023.102356] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 05/29/2023] [Accepted: 06/01/2023] [Indexed: 06/30/2023]
Abstract
Over the last several decades, there has been continued interest in developing novel therapeutic approaches targeting protein lysine methyltransferases (PKMTs). Along with PKMT inhibitors, targeted protein degradation (TPD) has emerged as a promising strategy to attenuate aberrant PKMT activity. Particularly, proteolysis targeting chimeras (PROTACs) effectively eliminate PKMTs of interest, suppressing all enzymatic and non-enzymatic functions. PROTACs and other TPD approaches add new depth to PKMT research and novel therapeutics discovery. This review focuses on recent advances in PKMT degrader and inhibitor development over the last several years.
Collapse
Affiliation(s)
- Julia Velez
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - H Ümit Kaniskan
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
| | - Jian Jin
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
| |
Collapse
|
|
24
|
Zhu JY, van de Leemput J, Han Z. The Roles of Histone Lysine Methyltransferases in Heart Development and Disease. J Cardiovasc Dev Dis 2023; 10:305. [PMID: 37504561 PMCID: PMC10380575 DOI: 10.3390/jcdd10070305] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/10/2023] [Accepted: 07/13/2023] [Indexed: 07/29/2023] Open
Abstract
Epigenetic marks regulate the transcriptomic landscape by facilitating the structural packing and unwinding of the genome, which is tightly folded inside the nucleus. Lysine-specific histone methylation is one such mark. It plays crucial roles during development, including in cell fate decisions, in tissue patterning, and in regulating cellular metabolic processes. It has also been associated with varying human developmental disorders. Heart disease has been linked to deregulated histone lysine methylation, and lysine-specific methyltransferases (KMTs) are overrepresented, i.e., more numerous than expected by chance, among the genes with variants associated with congenital heart disease. This review outlines the available evidence to support a role for individual KMTs in heart development and/or disease, including genetic associations in patients and supporting cell culture and animal model studies. It concludes with new advances in the field and new opportunities for treatment.
Collapse
Affiliation(s)
- Jun-yi Zhu
- Center for Precision Disease Modeling, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Joyce van de Leemput
- Center for Precision Disease Modeling, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Zhe Han
- Center for Precision Disease Modeling, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| |
Collapse
|
|
25
|
Maritz C, Khaleghi R, Yancoskie MN, Diethelm S, Brülisauer S, Ferreira NS, Jiang Y, Sturla SJ, Naegeli H. ASH1L-MRG15 methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair. Nat Commun 2023; 14:3892. [PMID: 37393406 PMCID: PMC10314917 DOI: 10.1038/s41467-023-39635-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 06/22/2023] [Indexed: 07/03/2023] Open
Abstract
To recognize DNA adducts, nucleotide excision repair (NER) deploys the XPC sensor, which detects damage-induced helical distortions, followed by engagement of TFIIH for lesion verification. Accessory players ensure that this factor handover takes place in chromatin where DNA is tightly wrapped around histones. Here, we describe how the histone methyltransferase ASH1L, once activated by MRG15, helps XPC and TFIIH to navigate through chromatin and induce global-genome NER hotspots. Upon UV irradiation, ASH1L adds H3K4me3 all over the genome (except in active gene promoters), thus priming chromatin for XPC relocations from native to damaged DNA. The ASH1L-MRG15 complex further recruits the histone chaperone FACT to DNA lesions. In the absence of ASH1L, MRG15 or FACT, XPC is misplaced and persists on damaged DNA without being able to deliver the lesions to TFIIH. We conclude that ASH1L-MRG15 makes damage verifiable by the NER machinery through the sequential deposition of H3K4me3 and FACT.
Collapse
Affiliation(s)
- Corina Maritz
- Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland
| | - Reihaneh Khaleghi
- Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland
| | - Michelle N Yancoskie
- Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland
| | - Sarah Diethelm
- Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland
| | - Sonja Brülisauer
- Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland
| | - Natalia Santos Ferreira
- Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland
| | - Yang Jiang
- Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
| | - Shana J Sturla
- Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
| | - Hanspeter Naegeli
- Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.
| |
Collapse
|
|
26
|
Xiu S, Chi X, Jia Z, Shi C, Zhang X, Li Q, Gao T, Zhang L, Liu Z. NSD3: Advances in cancer therapeutic potential and inhibitors research. Eur J Med Chem 2023; 256:115440. [PMID: 37182335 DOI: 10.1016/j.ejmech.2023.115440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 04/27/2023] [Accepted: 04/30/2023] [Indexed: 05/16/2023]
Abstract
Nuclear receptor-binding SET domain 3, otherwise known as NSD3, is a member of the group of lysine methyltransferases and is involved in a variety of cellular processes, including transcriptional regulation, DNA damage repair, non-histone related functions and several others. NSD3 gene is mutated or loss of function in a variety of cancers, including breast, lung, pancreatic, and osteosarcoma. These mutations produce dysfunction of the corresponding tumor tissue proteins, leading to tumorigenesis, progression, chemoresistance, and unfavorable prognosis, which suggests that the development of NSD3 probe molecules is important for understanding the specific role of NSD3 in disease and drug discovery. In recent years, NSD3 has been increasingly reported, demonstrating that this target is a very hot epigenetic target. However, the number of NSD3 inhibitors available for cancer therapy is limited and none of the drugs that target NSD3 are currently available on the market. In addition, there are very few reviews describing NSD3. Within this review, we highlight the role of NSD3 in tumorigenesis and the development of NSD3 targeted small-molecule inhibitors over the last decade. We hope that this publication can serve as a guide for the development of potential drug candidates for various diseases in the field of epigenetics, especially for the NSD3 target.
Collapse
Affiliation(s)
- Siyu Xiu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China
| | - Xiaowei Chi
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China
| | - Zhenyu Jia
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China
| | - Cheng Shi
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China
| | - Xiangyu Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China
| | - Qi Li
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China
| | - Tongfei Gao
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China
| | - Liangren Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
| | - Zhenming Liu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
| |
Collapse
|
|
27
|
Tang XF, Huang YH, Sun YF, Zhang PF, Huo LZ, Li HS, Pang H. The transcriptome of Icerya aegyptiaca (Hemiptera: Monophlebidae) and comparison with neococcoids reveal genetic clues of evolution in the scale insects. BMC Genomics 2023; 24:231. [PMID: 37138224 PMCID: PMC10158165 DOI: 10.1186/s12864-023-09327-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Accepted: 04/21/2023] [Indexed: 05/05/2023] Open
Abstract
BACKGROUND Scale insects are worldwide sap-sucking parasites, which can be distinguished into neococcoids and non-neococcoids. Neococcoids are monophyletic with a peculiar reproductive system, paternal genome elimination (PGE). Different with neococcoids, Iceryini, a tribe in non-neococcoids including several damaging pests, has abdominal spiracles, compound eyes in males, relatively abundant wax, unique hermaphrodite system, and specific symbionts. However, the current studies on the gene resources and genomic mechanism of scale insects are mainly limited in the neococcoids, and lacked of comparison in an evolution frame. RESULT We sequenced and de novo assembled a transcriptome of Icerya aegyptiaca (Douglas), a worldwide pest of Iceryini, and used it as representative of non-neococcoids to compare with the genomes or transcriptomes of other six species from different families of neococcoids. We found that the genes under positive selection or negative selection intensification (simplified as "selected genes" below) in I. aegyptiaca included those related to neurogenesis and development, especially eye development. Some genes related to fatty acid biosynthesis were unique in its transcriptome with relatively high expression and not detected in neococcoids. These results may indicate a potential link to the unique structures and abundant wax of I. aegyptiaca compared with neococcoids. Meanwhile, genes related to DNA repair, mitosis, spindle, cytokinesis and oogenesis, were included in the selected genes in I. aegyptiaca, which is possibly associated with cell division and germ cell formation of the hermaphrodite system. Chromatin-related process were enriched from selected genes in neococcoids, along with some mitosis-related genes also detected, which may be related to their unique PGE system. Moreover, in neococcoid species, male-biased genes tend to undergo negative selection relaxation under the PGE system. We also found that the candidate horizontally transferred genes (HTGs) in the scale insects mainly derived from bacteria and fungi. bioD and bioB, the two biotin-synthesizing HTGs were exclusively found in the scale insects and neococcoids, respectively, which possibly show potential demand changes in the symbiotic relationships. CONCLUSION Our study reports the first I. aegyptiaca transcriptome and provides preliminary insights for the genetic change of structures, reproductive systems and symbiont relationships at an evolutionary aspect. This will provide a basis for further research and control of scale insects.
Collapse
Affiliation(s)
- Xue-Fei Tang
- State Key Laboratory of Biocontrol, School of Ecology, Sun Yat-Sen University, Shenzhen, China
| | - Yu-Hao Huang
- State Key Laboratory of Biocontrol, School of Ecology, Sun Yat-Sen University, Shenzhen, China
| | - Yi-Fei Sun
- State Key Laboratory of Biocontrol, School of Ecology, Sun Yat-Sen University, Shenzhen, China
| | - Pei-Fang Zhang
- State Key Laboratory of Biocontrol, School of Ecology, Sun Yat-Sen University, Shenzhen, China
| | - Li-Zhi Huo
- Guangzhou Institute of Forestry and Landscape Architecture, Guangzhou, China
| | - Hao-Sen Li
- State Key Laboratory of Biocontrol, School of Ecology, Sun Yat-Sen University, Shenzhen, China
| | - Hong Pang
- State Key Laboratory of Biocontrol, School of Ecology, Sun Yat-Sen University, Shenzhen, China.
| |
Collapse
|
|
28
|
Yoon E, Song JJ. Caf1 regulates the histone methyltransferase activity of Ash1 by sensing unmodified histone H3. Epigenetics Chromatin 2023; 16:15. [PMID: 37118845 PMCID: PMC10148413 DOI: 10.1186/s13072-023-00487-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 04/17/2023] [Indexed: 04/30/2023] Open
Abstract
Histone modifications are one of the many key mechanisms that regulate gene expression. Ash1 is a histone H3K36 methyltransferase and is involved in gene activation. Ash1 forms a large complex with Mrg15 and Caf1/p55/Nurf55/RbAp48 (AMC complex). The Ash1 subunit alone exhibits very low activity due to the autoinhibition, and the binding of Mrg15 releases the autoinhibition. Caf1 is a scaffolding protein commonly found in several chromatin modifying complexes and has two histone binding pockets: one for H3 and the other for H4. Caf1 has the ability to sense unmodified histone H3K4 residues using the H3 binding pocket. However, the role of Caf1 in the AMC complex has not been investigated. Here, we dissected the interaction among the AMC complex subunits, revealing that Caf1 uses the histone H4 binding pocket to interact with Ash1 near the histone binding module cluster. Furthermore, we showed that H3K4 methylation inhibits AMC HMTase activity via Caf1 sensing unmodified histone H3K4 to regulate the activity in an internucleosomal manner, suggesting that crosstalk between H3K4 and H3K36 methylation. Our work revealed a delicate mechanism by which the AMC histone H3K36 methyltransferase complex is regulated.
Collapse
Affiliation(s)
- Eojin Yoon
- Department of Biological Sciences, KI for BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea
| | - Ji-Joon Song
- Department of Biological Sciences, KI for BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea.
| |
Collapse
|
|
29
|
Yancoskie MN, Maritz C, van Eijk P, Reed SH, Naegeli H. To incise or not and where: SET-domain methyltransferases know. Trends Biochem Sci 2023; 48:321-330. [PMID: 36357311 DOI: 10.1016/j.tibs.2022.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 10/10/2022] [Accepted: 10/14/2022] [Indexed: 11/09/2022]
Abstract
The concept of the histone code posits that histone modifications regulate gene functions once interpreted by epigenetic readers. A well-studied case is trimethylation of lysine 4 of histone H3 (H3K4me3), which is enriched at gene promoters. However, H3K4me3 marks are not needed for the expression of most genes, suggesting extra roles, such as influencing the 3D genome architecture. Here, we highlight an intriguing analogy between the H3K4me3-dependent induction of double-strand breaks in several recombination events and the impact of this same mark on DNA incisions for the repair of bulky lesions. We propose that Su(var)3-9, Enhancer-of-zeste and Trithorax (SET)-domain methyltransferases generate H3K4me3 to guide nucleases into chromatin spaces, the favorable accessibility of which ensures that DNA break intermediates are readily processed, thereby safeguarding genome stability.
Collapse
Affiliation(s)
- Michelle N Yancoskie
- Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland
| | - Corina Maritz
- Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland
| | - Patrick van Eijk
- Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK
| | - Simon H Reed
- Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK
| | - Hanspeter Naegeli
- Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.
| |
Collapse
|
|
30
|
Zhang Y, Zhang Q, Zhang Y, Han J. The Role of Histone Modification in DNA Replication-Coupled Nucleosome Assembly and Cancer. Int J Mol Sci 2023; 24:ijms24054939. [PMID: 36902370 PMCID: PMC10003558 DOI: 10.3390/ijms24054939] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/28/2023] [Accepted: 01/29/2023] [Indexed: 03/08/2023] Open
Abstract
Histone modification regulates replication-coupled nucleosome assembly, DNA damage repair, and gene transcription. Changes or mutations in factors involved in nucleosome assembly are closely related to the development and pathogenesis of cancer and other human diseases and are essential for maintaining genomic stability and epigenetic information transmission. In this review, we discuss the role of different types of histone posttranslational modifications in DNA replication-coupled nucleosome assembly and disease. In recent years, histone modification has been found to affect the deposition of newly synthesized histones and the repair of DNA damage, further affecting the assembly process of DNA replication-coupled nucleosomes. We summarize the role of histone modification in the nucleosome assembly process. At the same time, we review the mechanism of histone modification in cancer development and briefly describe the application of histone modification small molecule inhibitors in cancer therapy.
Collapse
|
|
31
|
Xie SS, Zhang YZ, Peng L, Yu DT, Zhu G, Zhao Q, Wang CH, Xie Q, Duan CG. JMJ28 guides sequence-specific targeting of ATX1/2-containing COMPASS-like complex in Arabidopsis. Cell Rep 2023; 42:112163. [PMID: 36827182 DOI: 10.1016/j.celrep.2023.112163] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 09/21/2022] [Accepted: 02/09/2023] [Indexed: 02/25/2023] Open
Abstract
Despite extensive investigations in mammals and yeasts, the importance and specificity of COMPASS-like complex, which catalyzes histone 3 lysine 4 methylation (H3K4me), are not fully understood in plants. Here, we report that JMJ28, a Jumonji C domain-containing protein in Arabidopsis, recognizes specific DNA motifs through a plant-specific WRC domain and acts as an interacting factor to guide the chromatin targeting of ATX1/2-containing COMPASS-like complex. JMJ28 associates with COMPASS-like complex in vivo via direct interaction with RBL. The DNA-binding activity of JMJ28 is essential for both the targeting specificity of ATX1/2-COMPASS and the deposition of H3K4me at specific loci but exhibit functional redundancy with alternative COMPASS-like complexes at other loci. Finally, we demonstrate that JMJ28 is a negative regulator of plant immunity. In summary, our findings reveal a plant-specific recruitment mechanism of COMPASS-like complex. These findings help to gain deeper insights into the regulatory mechanism of COMPASS-like complex in plants.
Collapse
Affiliation(s)
- Si-Si Xie
- Shanghai Center for Plant Stress Biology and CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai 200032, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yi-Zhe Zhang
- Shanghai Center for Plant Stress Biology and CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai 200032, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Li Peng
- Shanghai Center for Plant Stress Biology and CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai 200032, China
| | - Ding-Tian Yu
- Shanghai Center for Plant Stress Biology and CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai 200032, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Guohui Zhu
- College of Life Sciences, South China Agricultural University, Guangzhou 510642, China
| | - Qingzhen Zhao
- School of Life Sciences, Liaocheng University, Liaocheng 252000, China
| | - Chun-Han Wang
- Shanghai Center for Plant Stress Biology and CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai 200032, China
| | - Qi Xie
- State Key Laboratory of Plant Genomics, Institute of Genetics and Developmental Biology, The Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing 100101, China
| | - Cheng-Guo Duan
- Shanghai Center for Plant Stress Biology and CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai 200032, China; University of Chinese Academy of Sciences, Beijing 100049, China.
| |
Collapse
|
|
32
|
Davis O. Abnormal Chromatin Folding in the Molecular Pathogenesis of Epilepsy and Autism Spectrum Disorder: a Meta-synthesis with Systematic Searching. Mol Neurobiol 2023; 60:768-779. [PMID: 36367658 PMCID: PMC9849311 DOI: 10.1007/s12035-022-03106-9] [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: 07/25/2022] [Accepted: 10/25/2022] [Indexed: 11/13/2022]
Abstract
How DNA is folded and packaged in nucleosomes is an essential regulator of gene expression. Abnormal patterns of chromatin folding are implicated in a wide range of diseases and disorders, including epilepsy and autism spectrum disorder (ASD). These disorders are thought to have a shared pathogenesis involving an imbalance in the number of excitatory-inhibitory neurons formed during neurodevelopment; however, the underlying pathological mechanism behind this imbalance is poorly understood. Studies are increasingly implicating abnormal chromatin folding in neural stem cells as one of the candidate pathological mechanisms, but no review has yet attempted to summarise the knowledge in this field. This meta-synthesis is a systematic search of all the articles on epilepsy, ASD, and chromatin folding. Its two main objectives were to determine to what extent abnormal chromatin folding is implicated in the pathogenesis of epilepsy and ASD, and secondly how abnormal chromatin folding leads to pathological disease processes. This search produced 22 relevant articles, which together strongly implicate abnormal chromatin folding in the pathogenesis of epilepsy and ASD. A range of mutations and chromosomal structural abnormalities lead to this effect, including single nucleotide polymorphisms, copy number variants, translocations and mutations in chromatin modifying. However, knowledge is much more limited into how abnormal chromatin organisation subsequently causes pathological disease processes, not yet showing, for example, whether it leads to abnormal excitation-inhibitory neuron imbalance in human brain organoids.
Collapse
Affiliation(s)
- Oliver Davis
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
| |
Collapse
|
|
33
|
Andricovich J, Tzatsos A. Biological Functions of the KDM2 Family of Histone Demethylases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1433:51-68. [PMID: 37751135 DOI: 10.1007/978-3-031-38176-8_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/27/2023]
Abstract
The histone lysine demethylase 2 (KDM2) family of α-Ketoglutarate-Fe++-dependent dioxygenases were the first Jumonji-domain-containing proteins reported to harbor demethylase activity. This landmark discovery paved the way for the characterization of more than 25 enzymes capable of demethylating lysine residues on histones-an epigenetic modification previously thought to be irreversible. The KDM2 family is comprised of KDM2A and KDM2B which share significant structural similarities and demethylate lysine 36 on histone H3. However, they exert distinct cellular functions and are frequently deregulated in a broad spectrum of human cancers. With the advent of next generation sequencing and development of genetically engineered mouse models, it was shown that KDM2A and KDM2B play critical roles in stem cell biology, somatic cell reprograming, and organismal development by regulating cell fate and lineage commitment decisions. Thus, understanding the biochemistry and elucidating the context-dependent function of these enzymes is an emerging new frontier for the development of small molecule inhibitors to treat cancer and other diseases.
Collapse
Affiliation(s)
- Jaclyn Andricovich
- Cancer Epigenetics Laboratory, George Washington University Cancer Center, 800 22nd St NW, Suite 8850, Washington DC, 20052, USA
| | - Alexandros Tzatsos
- Cancer Epigenetics Laboratory, George Washington University Cancer Center, 800 22nd St NW, Suite 8850, Washington DC, 20052, USA.
| |
Collapse
|
|
34
|
Markouli M, Strepkos D, Piperi C. Impact of Histone Modifications and Their Therapeutic Targeting in Hematological Malignancies. Int J Mol Sci 2022; 23:13657. [PMID: 36362442 PMCID: PMC9654260 DOI: 10.3390/ijms232113657] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/31/2022] [Accepted: 11/02/2022] [Indexed: 11/09/2022] Open
Abstract
Hematologic malignancies are a large and heterogeneous group of neoplasms characterized by complex pathogenetic mechanisms. The abnormal regulation of epigenetic mechanisms and specifically, histone modifications, has been demonstrated to play a central role in hematological cancer pathogenesis and progression. A variety of epigenetic enzymes that affect the state of histones have been detected as deregulated, being either over- or underexpressed, which induces changes in chromatin compaction and, subsequently, affects gene expression. Recent advances in the field of epigenetics have revealed novel therapeutic targets, with many epigenetic drugs being investigated in clinical trials. The present review focuses on the biological impact of histone modifications in the pathogenesis of hematologic malignancies, describing a wide range of therapeutic agents that have been discovered to target these alterations and are currently under investigation in clinical trials.
Collapse
Affiliation(s)
| | | | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.M.); (D.S.)
| |
Collapse
|
|
35
|
Koyauchi T, Niida H, Motegi A, Sakai S, Uchida C, Ohhata T, Iijima K, Yokoyama A, Suda T, Kitagawa M. Chromatin-remodeling factor BAZ1A/ACF1 targets UV damage sites in an MLL1-dependent manner to facilitate nucleotide excision repair. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2022; 1869:119332. [PMID: 35940372 DOI: 10.1016/j.bbamcr.2022.119332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 07/25/2022] [Accepted: 07/28/2022] [Indexed: 06/15/2023]
Abstract
Ultraviolet (UV) light irradiation generates pyrimidine dimers on DNA, such as cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts. Such dimers distort the high-order DNA structure and prevent transcription and replication. The nucleotide excision repair (NER) system contributes to resolving this type of DNA lesion. There are two pathways that recognize pyrimidine dimers. One acts on transcribed strands of DNA (transcription-coupled NER), and the other acts on the whole genome (global genome-NER; GG-NER). In the latter case, DNA damage-binding protein 2 (DDB2) senses pyrimidine dimers with several histone modification enzymes. We previously reported that histone acetyltransferase binding to ORC1 (HBO1) interacts with DDB2 and facilitates recruitment of the imitation switch chromatin remodeler at UV-irradiated sites via an unknown methyltransferase. Here, we found that the phosphorylated histone methyltransferase mixed lineage leukemia 1 (MLL1) was maintained at UV-irradiated sites in an HBO1-dependent manner. Furthermore, MLL1 catalyzed histone H3K4 methylation and recruited the chromatin remodeler bromodomain adjacent to zinc finger domain 1A (BAZ1A)/ATP-utilizing chromatin assembly and remodeling factor 1 (ACF1). Depletion of MLL1 suppressed BAZ1A accumulation at UV-irradiated sites and inhibited the removal of CPDs. These data indicate that the DDB2-HBO1-MLL1 axis is essential for the recruitment of BAZ1A to facilitate GG-NER.
Collapse
Affiliation(s)
- Takafumi Koyauchi
- Department of Molecular Biology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan; Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Hiroyuki Niida
- Department of Molecular Biology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan.
| | - Akira Motegi
- Department of Radiation Genetics, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Satoshi Sakai
- Department of Molecular Biology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Chiharu Uchida
- Advanced Research Facilities and Services, Preeminent Medical Photonics Education and Research Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Tatsuya Ohhata
- Department of Molecular Biology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Kenta Iijima
- Laboratory Animal Facilities and Services, Preeminent Medical Photonics Education and Research Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Akihiko Yokoyama
- Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Yamagata 997-0052, Japan
| | - Takafumi Suda
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Masatoshi Kitagawa
- Department of Molecular Biology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| |
Collapse
|
|
36
|
Xiong X, Zhang X, Yang M, Zhu Y, Yu H, Fei X, Mastuda F, Lan D, Xiong Y, Fu W, Yin S, Li J. Oocyte-Specific Knockout of Histone Lysine Demethylase KDM2a Compromises Fertility by Blocking the Development of Follicles and Oocytes. Int J Mol Sci 2022; 23:ijms231912008. [PMID: 36233308 PMCID: PMC9570323 DOI: 10.3390/ijms231912008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/07/2022] [Accepted: 10/07/2022] [Indexed: 11/05/2022] Open
Abstract
The methylation status of histones plays a crucial role in many cellular processes, including follicular and oocyte development. Lysine-specific demethylase 2a (KDM2a) has been reported to be closely associated with gametogenesis and reproductive performance, but the specific function and regulatory mechanism have been poorly characterized in vivo. We found KDM2a to be highly expressed in growing follicles and oocytes of mice in this study. To elucidate the physiological role of Kdm2a, the zona pellucida 3-Cre (Zp3-Cre)/LoxP system was used to generate an oocyte Kdm2a conditional knockout (Zp3-Cre; Kdm2aflox/flox, termed Kdm2a cKO) model. Our results showed that the number of pups was reduced by approximately 50% in adult Kdm2a cKO female mice mating with wildtype males than that of the control (Kdm2aflox/flox) group. To analyze the potential causes, the ovaries of Kdm2a cKO mice were subjected to histological examination, and results indicated an obvious difference in follicular development between Kdm2a cKO and control female mice and partial arrest at the primary antral follicle stage. The GVBD and matured rates of oocytes were also compromised after conditional knockout Kdm2a, and the morphological abnormal oocytes increased. Furthermore, the level of 17β-estradiol of Kdm2a cKO mice was only 60% of that in the counterparts, and hormone sensitivity decreased as the total number of ovulated and matured oocytes decreased after superovulation. After deletion of Kdm2a, the patterns of H3K36me2/3 in GVBD-stage oocytes were remarkedly changed. Transcriptome sequencing showed that the mRNA expression profiles in Kdm2a cKO oocytes were significantly different, and numerous differentially expressed genes were involved in pathways regulating follicular and oocyte development. Taken together, these results indicated that the oocyte-specific knockout Kdm2a gene led to female subfertility, suggesting the crucial role of Kdm2a in epigenetic modification and follicular and oocyte development.
Collapse
Affiliation(s)
- Xianrong Xiong
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China
- Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu 610041, China
| | - Xiaojian Zhang
- Center for Assisted Reproduction, Sichuan Academy of Medical Science, Sichuan Provincial People’s Hospital, Chengdu 610072, China
| | - Manzhen Yang
- Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu 610041, China
| | - Yanjin Zhu
- Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu 610041, China
| | - Hailing Yu
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China
| | - Xixi Fei
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China
| | - Fuko Mastuda
- Laboratory of Theriogenology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan
| | - Daoliang Lan
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China
| | - Yan Xiong
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China
| | - Wei Fu
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China
| | - Shi Yin
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China
| | - Jian Li
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China
- Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu 610041, China
- Correspondence:
| |
Collapse
|
|
37
|
Song S, Creus Muncunill J, Galicia Aguirre C, Tshilenge KT, Hamilton BW, Gerencser AA, Benlhabib H, Cirnaru MD, Leid M, Mooney SD, Ellerby LM, Ehrlich ME. Postnatal Conditional Deletion of Bcl11b in Striatal Projection Neurons Mimics the Transcriptional Signature of Huntington's Disease. Biomedicines 2022; 10:2377. [PMID: 36289639 PMCID: PMC9598565 DOI: 10.3390/biomedicines10102377] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/15/2022] [Accepted: 08/19/2022] [Indexed: 11/16/2022] Open
Abstract
The dysregulation of striatal gene expression and function is linked to multiple diseases, including Huntington's disease (HD), Parkinson's disease, X-linked dystonia-parkinsonism (XDP), addiction, autism, and schizophrenia. Striatal medium spiny neurons (MSNs) make up 90% of the neurons in the striatum and are critical to motor control. The transcription factor, Bcl11b (also known as Ctip2), is required for striatal development, but the function of Bcl11b in adult MSNs in vivo has not been investigated. We conditionally deleted Bcl11b specifically in postnatal MSNs and performed a transcriptomic and behavioral analysis on these mice. Multiple enrichment analyses showed that the D9-Cre-Bcl11btm1.1Leid transcriptional profile was similar to the HD gene expression in mouse and human data sets. A Gene Ontology enrichment analysis linked D9-Cre-Bcl11btm1.1Leid to calcium, synapse organization, specifically including the dopaminergic synapse, protein dephosphorylation, and HDAC-signaling, commonly dysregulated pathways in HD. D9-Cre-Bcl11btm1.1Leid mice had decreased DARPP-32/Ppp1r1b in MSNs and behavioral deficits, demonstrating the dysregulation of a subtype of the dopamine D2 receptor expressing MSNs. Finally, in human HD isogenic MSNs, the mislocalization of BCL11B into nuclear aggregates points to a mechanism for BCL11B loss of function in HD. Our results suggest that BCL11B is important for the function and maintenance of mature MSNs and Bcl11b loss of function drives, in part, the transcriptomic and functional changes in HD.
Collapse
Affiliation(s)
- Sicheng Song
- Department of Biomedical Informatics and Medical Education, School of Medicine, University of Washington, Seattle, WA 98109, USA
| | - Jordi Creus Muncunill
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Carlos Galicia Aguirre
- Buck Institute for Research on Aging, Novato, CA 94945, USA
- Leonard Davis School of Gerontology, University of Southern California, 3715 McClintock Ave, Los Angeles, CA 90893, USA
| | | | - B. Wade Hamilton
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | | | - Houda Benlhabib
- Department of Biomedical Informatics and Medical Education, School of Medicine, University of Washington, Seattle, WA 98109, USA
| | - Maria-Daniela Cirnaru
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Mark Leid
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA
| | - Sean D. Mooney
- Department of Biomedical Informatics and Medical Education, School of Medicine, University of Washington, Seattle, WA 98109, USA
| | - Lisa M. Ellerby
- Buck Institute for Research on Aging, Novato, CA 94945, USA
- Leonard Davis School of Gerontology, University of Southern California, 3715 McClintock Ave, Los Angeles, CA 90893, USA
| | - Michelle E. Ehrlich
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| |
Collapse
|
|
38
|
Yu M, Jia Y, Ma Z, Ji D, Wang C, Liang Y, Zhang Q, Yi H, Zeng L. Structural insight into ASH1L PHD finger recognizing methylated histone H3K4 and promoting cell growth in prostate cancer. Front Oncol 2022; 12:906807. [PMID: 36033518 PMCID: PMC9399681 DOI: 10.3389/fonc.2022.906807] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 07/19/2022] [Indexed: 11/17/2022] Open
Abstract
ASH1L is a member of the Trithorax-group protein and acts as a histone methyltransferase for gene transcription activation. It is known that ASH1L modulates H3K4me3 and H3K36me2/3 at its gene targets, but its specific mechanism of histone recognition is insufficiently understood. In this study, we found that the ASH1L plant homeodomain (PHD) finger interacts with mono-, di-, and trimethylated states of H3K4 peptides with comparable affinities, indicating that ASH1L PHD non-selectively binds to all three methylation states of H3K4. We solved nuclear magnetic resonance structures picturing the ASH1L PHD finger binding to the dimethylated H3K4 peptide and found that a narrow binding groove and residue composition in the methylated-lysine binding pocket restricts the necessary interaction with the dimethyl-ammonium moiety of K4. In addition, we found that the ASH1L protein is overexpressed in castrate-resistant prostate cancer (PCa) PC3 and DU145 cells in comparison to PCa LNCaP cells. The knockdown of ASH1L modulated gene expression and cellular pathways involved in apoptosis and cell cycle regulation and consequently induced cell cycle arrest, cell apoptosis, and reduced colony-forming abilities in PC3 and DU145 cells. The overexpression of the C-terminal core of ASH1L but not the PHD deletion mutant increased the overall H3K36me2 level but had no effect on the H3K4me2/3 level. Overall, our study identifies the ASH1L PHD finger as the first native reader that non-selectively recognizes the three methylation states of H3K4. Additionally, ASH1L is required for the deregulation of cell cycle and survival in PCas.
Collapse
Affiliation(s)
- Miaomiao Yu
- Bethune Institute of Epigenetic Medicine, The First Hospital, Jilin University, Changchun, China
- International Center of Future Science, Jilin University, Changchun, China
| | - Yanjie Jia
- Bethune Institute of Epigenetic Medicine, The First Hospital, Jilin University, Changchun, China
| | - Zhanchuan Ma
- Central Laboratory, The First Hospital, Jilin University, Changchun, China
| | - Donglei Ji
- Bethune Institute of Epigenetic Medicine, The First Hospital, Jilin University, Changchun, China
- International Center of Future Science, Jilin University, Changchun, China
| | - Chunyu Wang
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun, China
| | - Yingying Liang
- Bethune Institute of Epigenetic Medicine, The First Hospital, Jilin University, Changchun, China
- International Center of Future Science, Jilin University, Changchun, China
| | - Qiang Zhang
- Bethune Institute of Epigenetic Medicine, The First Hospital, Jilin University, Changchun, China
| | - Huanfa Yi
- Central Laboratory, The First Hospital, Jilin University, Changchun, China
- *Correspondence: Huanfa Yi, ; Lei Zeng,
| | - Lei Zeng
- Bethune Institute of Epigenetic Medicine, The First Hospital, Jilin University, Changchun, China
- International Center of Future Science, Jilin University, Changchun, China
- *Correspondence: Huanfa Yi, ; Lei Zeng,
| |
Collapse
|
|
39
|
Park KS, Xiong Y, Yim H, Velez J, Babault N, Kumar P, Liu J, Jin J. Discovery of the First-in-Class G9a/GLP Covalent Inhibitors. J Med Chem 2022; 65:10506-10522. [PMID: 35763668 DOI: 10.1021/acs.jmedchem.2c00652] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The highly homologous protein lysine methyltransferases G9a and GLP, which catalyze mono- and dimethylation of histone H3 lysine 9 (H3K9), have been implicated in various human diseases. To investigate functions of G9a and GLP in human diseases, we and others reported several noncovalent reversible small-molecule inhibitors of G9a and GLP. Here, we report the discovery of the first-in-class G9a/GLP covalent irreversible inhibitors, 1 and 8 (MS8511), by targeting a cysteine residue at the substrate binding site. We characterized these covalent inhibitors in enzymatic, mass spectrometry based and cellular assays and using X-ray crystallography. Compared to the noncovalent G9a/GLP inhibitor UNC0642, covalent inhibitor 8 displayed improved potency in enzymatic and cellular assays. Interestingly, compound 8 also displayed potential kinetic preference for covalently modifying G9a over GLP. Collectively, compound 8 could be a useful chemical tool for studying the functional roles of G9a and GLP by covalently modifying and inhibiting these methyltransferases.
Collapse
Affiliation(s)
- Kwang-Su Park
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Yan Xiong
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Hyerin Yim
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Julia Velez
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Nicolas Babault
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Prashasti Kumar
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Jing Liu
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Jian Jin
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| |
Collapse
|
|
40
|
Histone H3K36me2 demethylase KDM2A promotes bladder cancer progression through epigenetically silencing RARRES3. Cell Death Dis 2022; 13:547. [PMID: 35697678 PMCID: PMC9192503 DOI: 10.1038/s41419-022-04983-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 05/22/2022] [Accepted: 05/26/2022] [Indexed: 01/21/2023]
Abstract
Epigenetic dysregulation contributes to bladder cancer tumorigenesis. H3K36me2 demethylase KDM2A functions as an important epigenetic regulator of cell fate in many types of tumors. However, its role in bladder cancer remains unknown. Here, we revealed a positive correlation between KDM2A gene copy number gain and upregulation of KDM2A mRNA expression in bladder cancer. Moreover, a super-enhancer (SE) driving KDM2A transcription was found in high-grade bladder cancer, resulting in a significantly higher expression of KDM2A mRNA compared to that in low-grade bladder tumors. KDM2A knockdown (KD) decreased the proliferation, invasion, and spheroid formation of high-grade bladder cancer cells and inhibited tumor growth in mouse xenograft models. Furthermore, we identified RARRES3 as a key KDM2A target gene. KDM2A suppresses RARRES3 expression via demethylation of H3K36me2 in the RARRES3 promoter. Intriguingly, RARRES3 KD attenuated the inhibitory effects of KDM2A depletion on the malignant phenotypes of high-grade bladder cancer cells. The combination of the KDM2A inhibitor IOX1 and the RARRES3 agonist all-trans retinoic acid (ATRA) synergistically inhibited the proliferation of high-grade bladder cancer cells, suggesting that the KDM2A/RARRES3 axis may be a promising therapeutic target for the treatment of high-grade bladder cancer.
Collapse
|
|
41
|
Devoucoux M, Roques C, Lachance C, Lashgari A, Joly-Beauparlant C, Jacquet K, Alerasool N, Prudente A, Taipale M, Droit A, Lambert JP, Hussein SMI, Côté J. MRG Proteins Are Shared by Multiple Protein Complexes With Distinct Functions. Mol Cell Proteomics 2022; 21:100253. [PMID: 35636729 PMCID: PMC9253478 DOI: 10.1016/j.mcpro.2022.100253] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 11/17/2022] Open
Abstract
MRG15/MORF4L1 is a highly conserved protein in eukaryotes that contains a chromodomain (CHD) recognizing methylation of lysine 36 on histone H3 (H3K36me3) in chromatin. Intriguingly, it has been reported in the literature to interact with several different factors involved in chromatin modifications, gene regulation, alternative mRNA splicing, and DNA repair by homologous recombination. To get a complete and reliable picture of associations in physiological conditions, we used genome editing and tandem affinity purification to analyze the stable native interactome of human MRG15, its paralog MRGX/MORF4L2 that lacks the CHD, and MRGBP (MRG-binding protein) in isogenic K562 cells. We found stable interchangeable association of MRG15 and MRGX with the NuA4/TIP60 histone acetyltransferase/chromatin remodeler, Sin3B histone deacetylase/demethylase, ASH1L histone methyltransferase, and PALB2-BRCA2 DNA repair protein complexes. These associations were further confirmed and analyzed by CRISPR tagging of endogenous proteins and comparison of expressed isoforms. Importantly, based on structural information, point mutations could be introduced that specifically disrupt MRG15 association with some complexes but not others. Most interestingly, we also identified a new abundant native complex formed by MRG15/X-MRGBP-BRD8-EP400NL (EP400 N-terminal like) that is functionally similar to the yeast TINTIN (Trimer Independent of NuA4 for Transcription Interactions with Nucleosomes) complex. Our results show that EP400NL, being homologous to the N-terminal region of NuA4/TIP60 subunit EP400, creates TINTIN by competing for BRD8 association. Functional genomics indicate that human TINTIN plays a role in transcription of specific genes. This is most likely linked to the H4ac-binding bromodomain of BRD8 along the H3K36me3-binding CHD of MRG15 on the coding region of transcribed genes. Taken together, our data provide a complete detailed picture of human MRG proteins-associated protein complexes, which are essential to understand and correlate their diverse biological functions in chromatin-based nuclear processes.
Collapse
Affiliation(s)
- Maëva Devoucoux
- St. Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Oncology Division of CHU de Québec-Université Laval Research Center, Quebec City, Quebec, Canada
| | - Céline Roques
- St. Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Oncology Division of CHU de Québec-Université Laval Research Center, Quebec City, Quebec, Canada
| | - Catherine Lachance
- St. Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Oncology Division of CHU de Québec-Université Laval Research Center, Quebec City, Quebec, Canada
| | - Anahita Lashgari
- St. Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Oncology Division of CHU de Québec-Université Laval Research Center, Quebec City, Quebec, Canada; Department of Molecular Medicine, Laval University Cancer Research Center, CHU de Québec-Université Laval Research Center, Big Data Research Center, Université Laval, Quebec City, Quebec, Canada
| | - Charles Joly-Beauparlant
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Pavillon CHUL, Quebec City, Quebec, Canada; Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada
| | - Karine Jacquet
- St. Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Oncology Division of CHU de Québec-Université Laval Research Center, Quebec City, Quebec, Canada
| | - Nader Alerasool
- Department of Molecular Genetics, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada
| | - Alexandre Prudente
- St. Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Oncology Division of CHU de Québec-Université Laval Research Center, Quebec City, Quebec, Canada
| | - Mikko Taipale
- Department of Molecular Genetics, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada
| | - Arnaud Droit
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Pavillon CHUL, Quebec City, Quebec, Canada; Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada
| | - Jean-Philippe Lambert
- Department of Molecular Medicine, Laval University Cancer Research Center, CHU de Québec-Université Laval Research Center, Big Data Research Center, Université Laval, Quebec City, Quebec, Canada
| | - Samer M I Hussein
- St. Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Oncology Division of CHU de Québec-Université Laval Research Center, Quebec City, Quebec, Canada
| | - Jacques Côté
- St. Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Oncology Division of CHU de Québec-Université Laval Research Center, Quebec City, Quebec, Canada.
| |
Collapse
|
|
42
|
Lam UTF, Tan BKY, Poh JJX, Chen ES. Structural and functional specificity of H3K36 methylation. Epigenetics Chromatin 2022; 15:17. [PMID: 35581654 PMCID: PMC9116022 DOI: 10.1186/s13072-022-00446-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 04/04/2022] [Indexed: 12/20/2022] Open
Abstract
The methylation of histone H3 at lysine 36 (H3K36me) is essential for maintaining genomic stability. Indeed, this methylation mark is essential for proper transcription, recombination, and DNA damage response. Loss- and gain-of-function mutations in H3K36 methyltransferases are closely linked to human developmental disorders and various cancers. Structural analyses suggest that nucleosomal components such as the linker DNA and a hydrophobic patch constituted by histone H2A and H3 are likely determinants of H3K36 methylation in addition to the histone H3 tail, which encompasses H3K36 and the catalytic SET domain. Interaction of H3K36 methyltransferases with the nucleosome collaborates with regulation of their auto-inhibitory changes fine-tunes the precision of H3K36me in mediating dimethylation by NSD2 and NSD3 as well as trimethylation by Set2/SETD2. The identification of specific structural features and various cis-acting factors that bind to different forms of H3K36me, particularly the di-(H3K36me2) and tri-(H3K36me3) methylated forms of H3K36, have highlighted the intricacy of H3K36me functional significance. Here, we consolidate these findings and offer structural insight to the regulation of H3K36me2 to H3K36me3 conversion. We also discuss the mechanisms that underlie the cooperation between H3K36me and other chromatin modifications (in particular, H3K27me3, H3 acetylation, DNA methylation and N6-methyladenosine in RNAs) in the physiological regulation of the epigenomic functions of chromatin.
Collapse
Affiliation(s)
- Ulysses Tsz Fung Lam
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Bryan Kok Yan Tan
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - John Jia Xin Poh
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Ee Sin Chen
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- National University Health System (NUHS), Singapore, Singapore.
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Integrative Sciences & Engineering Programme, National University of Singapore, Singapore, Singapore.
| |
Collapse
|
|
43
|
Cheon S, Culver AM, Bagnell AM, Ritchie FD, Vacharasin JM, McCord MM, Papendorp CM, Chukwurah E, Smith AJ, Cowen MH, Moreland TA, Ghate PS, Davis SW, Liu JS, Lizarraga SB. Counteracting epigenetic mechanisms regulate the structural development of neuronal circuitry in human neurons. Mol Psychiatry 2022; 27:2291-2303. [PMID: 35210569 PMCID: PMC9133078 DOI: 10.1038/s41380-022-01474-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 02/02/2022] [Indexed: 01/23/2023]
Abstract
Autism spectrum disorders (ASD) are associated with defects in neuronal connectivity and are highly heritable. Genetic findings suggest that there is an overrepresentation of chromatin regulatory genes among the genes associated with ASD. ASH1 like histone lysine methyltransferase (ASH1L) was identified as a major risk factor for ASD. ASH1L methylates Histone H3 on Lysine 36, which is proposed to result primarily in transcriptional activation. However, how mutations in ASH1L lead to deficits in neuronal connectivity associated with ASD pathogenesis is not known. We report that ASH1L regulates neuronal morphogenesis by counteracting the catalytic activity of Polycomb Repressive complex 2 group (PRC2) in stem cell-derived human neurons. Depletion of ASH1L decreases neurite outgrowth and decreases expression of the gene encoding the neurotrophin receptor TrkB whose signaling pathway is linked to neuronal morphogenesis. The neuronal morphogenesis defect is overcome by inhibition of PRC2 activity, indicating that a balance between the Trithorax group protein ASH1L and PRC2 activity determines neuronal morphology. Thus, our work suggests that ASH1L may epigenetically regulate neuronal morphogenesis by modulating pathways like the BDNF-TrkB signaling pathway. Defects in neuronal morphogenesis could potentially impair the establishment of neuronal connections which could contribute to the neurodevelopmental pathogenesis associated with ASD in patients with ASH1L mutations.
Collapse
Affiliation(s)
- Seonhye Cheon
- Department of Biological Sciences, University of South Carolina, Columbia, SC, USA
- Center for Childhood Neurotherapeutics, University of South Carolina, Columbia, SC, USA
| | - Allison M Culver
- Department of Biological Sciences, University of South Carolina, Columbia, SC, USA
- Center for Childhood Neurotherapeutics, University of South Carolina, Columbia, SC, USA
| | - Anna M Bagnell
- Department of Biological Sciences, University of South Carolina, Columbia, SC, USA
- Center for Childhood Neurotherapeutics, University of South Carolina, Columbia, SC, USA
| | - Foster D Ritchie
- Department of Biological Sciences, University of South Carolina, Columbia, SC, USA
- Center for Childhood Neurotherapeutics, University of South Carolina, Columbia, SC, USA
| | - Janay M Vacharasin
- Department of Biological Sciences, University of South Carolina, Columbia, SC, USA
- Center for Childhood Neurotherapeutics, University of South Carolina, Columbia, SC, USA
| | - Mikayla M McCord
- Department of Biological Sciences, University of South Carolina, Columbia, SC, USA
- Center for Childhood Neurotherapeutics, University of South Carolina, Columbia, SC, USA
| | - Carin M Papendorp
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA
| | - Evelyn Chukwurah
- Department of Biological Sciences, University of South Carolina, Columbia, SC, USA
- Center for Childhood Neurotherapeutics, University of South Carolina, Columbia, SC, USA
| | - Austin J Smith
- Department of Biological Sciences, University of South Carolina, Columbia, SC, USA
- Center for Childhood Neurotherapeutics, University of South Carolina, Columbia, SC, USA
| | - Mara H Cowen
- Department of Biological Sciences, University of South Carolina, Columbia, SC, USA
- Center for Childhood Neurotherapeutics, University of South Carolina, Columbia, SC, USA
| | - Trevor A Moreland
- Department of Biological Sciences, University of South Carolina, Columbia, SC, USA
- Center for Childhood Neurotherapeutics, University of South Carolina, Columbia, SC, USA
| | - Pankaj S Ghate
- Department of Biological Sciences, University of South Carolina, Columbia, SC, USA
- Center for Childhood Neurotherapeutics, University of South Carolina, Columbia, SC, USA
| | - Shannon W Davis
- Department of Biological Sciences, University of South Carolina, Columbia, SC, USA
- Center for Childhood Neurotherapeutics, University of South Carolina, Columbia, SC, USA
| | - Judy S Liu
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA
- Center for Translational Neuroscience, Robert J. and Nancy D. Carney Institute for Brain Science and Brown Institute for Translational Science, Brown University, Providence, RI, USA
- Department of Neurology, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Sofia B Lizarraga
- Department of Biological Sciences, University of South Carolina, Columbia, SC, USA.
- Center for Childhood Neurotherapeutics, University of South Carolina, Columbia, SC, USA.
| |
Collapse
|
|
44
|
Taylor-Papadimitriou J, Burchell JM. Histone Methylases and Demethylases Regulating Antagonistic Methyl Marks: Changes Occurring in Cancer. Cells 2022; 11:1113. [PMID: 35406676 PMCID: PMC8997813 DOI: 10.3390/cells11071113] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/17/2022] [Accepted: 03/22/2022] [Indexed: 02/06/2023] Open
Abstract
Epigenetic regulation of gene expression is crucial to the determination of cell fate in development and differentiation, and the Polycomb (PcG) and Trithorax (TrxG) groups of proteins, acting antagonistically as complexes, play a major role in this regulation. Although originally identified in Drosophila, these complexes are conserved in evolution and the components are well defined in mammals. Each complex contains a protein with methylase activity (KMT), which can add methyl groups to a specific lysine in histone tails, histone 3 lysine 27 (H3K27), by PcG complexes, and H3K4 and H3K36 by TrxG complexes, creating transcriptionally repressive or active marks, respectively. Histone demethylases (KDMs), identified later, added a new dimension to histone methylation, and mutations or changes in levels of expression are seen in both methylases and demethylases and in components of the PcG and TrX complexes across a range of cancers. In this review, we focus on both methylases and demethylases governing the methylation state of the suppressive and active marks and consider their action and interaction in normal tissues and in cancer. A picture is emerging which indicates that the changes which occur in cancer during methylation of histone lysines can lead to repression of genes, including tumour suppressor genes, or to the activation of oncogenes. Methylases or demethylases, which are themselves tumour suppressors, are highly mutated. Novel targets for cancer therapy have been identified and a methylase (KMT6A/EZH2), which produces the repressive H3K27me3 mark, and a demethylase (KDM1A/LSD1), which demethylates the active H3K4me2 mark, are now under clinical evaluation.
Collapse
|
|
45
|
Staehle HF, Pahl HL, Jutzi JS. The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies. Biomolecules 2021; 11:biom11121911. [PMID: 34944554 PMCID: PMC8699298 DOI: 10.3390/biom11121911] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/14/2021] [Accepted: 12/16/2021] [Indexed: 12/16/2022] Open
Abstract
Histone methylation tightly regulates chromatin accessibility, transcription, proliferation, and cell differentiation, and its perturbation contributes to oncogenic reprogramming of cells. In particular, many myeloid malignancies show evidence of epigenetic dysregulation. Jumonji C (JmjC) domain-containing proteins comprise a large and diverse group of histone demethylases (KDMs), which remove methyl groups from lysines in histone tails and other proteins. Cumulating evidence suggests an emerging role for these demethylases in myeloid malignancies, rendering them attractive targets for drug interventions. In this review, we summarize the known functions of Jumonji C (JmjC) domain-containing proteins in myeloid malignancies. We highlight challenges in understanding the context-dependent mechanisms of these proteins and explore potential future pharmacological targeting.
Collapse
Affiliation(s)
- Hans Felix Staehle
- Division of Molecular Hematology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79098 Freiburg, Germany; (H.F.S.); (H.L.P.)
| | - Heike Luise Pahl
- Division of Molecular Hematology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79098 Freiburg, Germany; (H.F.S.); (H.L.P.)
| | - Jonas Samuel Jutzi
- Division of Molecular Hematology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79098 Freiburg, Germany; (H.F.S.); (H.L.P.)
- Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston 02115, MA, USA
- Correspondence:
| |
Collapse
|
|
46
|
Yan F, Li J, Milosevic J, Petroni R, Liu S, Shi Z, Yuan S, Reynaga JM, Qi Y, Rico J, Yu S, Liu Y, Rokudai S, Palmisiano N, Meyer SE, Sung PJ, Wan L, Lan F, Garcia BA, Stanger BZ, Sykes DB, Blanco MA. KAT6A and ENL form an epigenetic transcriptional control module to drive critical leukemogenic gene expression programs. Cancer Discov 2021; 12:792-811. [PMID: 34853079 DOI: 10.1158/2159-8290.cd-20-1459] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 09/02/2021] [Accepted: 11/15/2021] [Indexed: 11/16/2022]
Abstract
Epigenetic programs are dysregulated in acute myeloid leukemia (AML) and help enforce an oncogenic state of differentiation arrest. To identify key epigenetic regulators of AML cell fate, we performed a differentiation-focused CRISPR screen in AML cells. This screen identified the histone acetyltransferase KAT6A as a novel regulator of myeloid differentiation that drives critical leukemogenic gene expression programs. We show that KAT6A is the initiator of a newly-described transcriptional control module in which KAT6A-catalyzed promoter H3K9ac is bound by the acetyllysine reader ENL, which in turn cooperates with a network of chromatin factors to induce transcriptional elongation. Inhibition of KAT6A has strong anti-AML phenotypes in vitro and in vivo, suggesting that KAT6A small molecule inhibitors could be of high therapeutic interest for mono or combinatorial differentiation-based treatment of AML.
Collapse
Affiliation(s)
- Fangxue Yan
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania
| | - Jinyang Li
- School of Medicine, University of Pennsylvania
| | - Jelena Milosevic
- Center for Regenerative Medicine, Massachusetts General Hospital
| | | | | | | | - Salina Yuan
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania
| | | | | | - Joshua Rico
- Biomedical Sciences, University of Pennsylvania
| | | | - Yiman Liu
- Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania
| | - Susumu Rokudai
- Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine
| | | | | | | | - Liling Wan
- Cancer Biology, Department of Cancer Biology, University of Pennsylvania; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania; Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania
| | - Fei Lan
- Institutes of Biomedical Sciences, Fudan University
| | - Benjamin A Garcia
- Department of Biochemistry and Biophysics, University of Pennsylvania
| | - Ben Z Stanger
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania
| | - David B Sykes
- Center for Regenerative Medicine, Massachusetts General Hospital
| | | |
Collapse
|
|
47
|
Aljazi MB, Gao Y, Wu Y, Mias GI, He J. Histone H3K36me2-Specific Methyltransferase ASH1L Promotes MLL-AF9-Induced Leukemogenesis. Front Oncol 2021; 11:754093. [PMID: 34692539 PMCID: PMC8534482 DOI: 10.3389/fonc.2021.754093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 09/17/2021] [Indexed: 01/19/2023] Open
Abstract
ASH1L and MLL1 are two histone methyltransferases that facilitate transcriptional activation during normal development. However, the roles of ASH1L and its enzymatic activity in the development of MLL-rearranged leukemias are not fully elucidated in Ash1L gene knockout animal models. In this study, we used an Ash1L conditional knockout mouse model to show that loss of ASH1L in hematopoietic progenitor cells impaired the initiation of MLL-AF9-induced leukemic transformation in vitro. Furthermore, genetic deletion of ASH1L in the MLL-AF9-transformed cells impaired the maintenance of leukemic cells in vitro and largely blocked the leukemia progression in vivo. Importantly, the loss of ASH1L function in the Ash1L-deleted cells could be rescued by wild-type but not the catalytic-dead mutant ASH1L, suggesting the enzymatic activity of ASH1L was required for its function in promoting MLL-AF9-induced leukemic transformation. At the molecular level, ASH1L enhanced the MLL-AF9 target gene expression by directly binding to the gene promoters and modifying the local histone H3K36me2 levels. Thus, our study revealed the critical functions of ASH1L in promoting the MLL-AF9-induced leukemogenesis, which provides a molecular basis for targeting ASH1L and its enzymatic activity to treat MLL-AF9-induced leukemias.
Collapse
Affiliation(s)
- Mohammad B Aljazi
- Department of Biochemistry and Molecular Biology, College of Nature Sciences, Michigan State University, East Lansing, MI, United States
| | - Yuen Gao
- Department of Biochemistry and Molecular Biology, College of Nature Sciences, Michigan State University, East Lansing, MI, United States
| | - Yan Wu
- Department of Biochemistry and Molecular Biology, College of Nature Sciences, Michigan State University, East Lansing, MI, United States
| | - George I Mias
- Department of Biochemistry and Molecular Biology, College of Nature Sciences, Michigan State University, East Lansing, MI, United States.,Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, United States
| | - Jin He
- Department of Biochemistry and Molecular Biology, College of Nature Sciences, Michigan State University, East Lansing, MI, United States
| |
Collapse
|
|
48
|
Li W, Wu H, Sui S, Wang Q, Xu S, Pang D. Targeting Histone Modifications in Breast Cancer: A Precise Weapon on the Way. Front Cell Dev Biol 2021; 9:736935. [PMID: 34595180 PMCID: PMC8476812 DOI: 10.3389/fcell.2021.736935] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 08/16/2021] [Indexed: 12/27/2022] Open
Abstract
Histone modifications (HMs) contribute to maintaining genomic stability, transcription, DNA repair, and modulating chromatin in cancer cells. Furthermore, HMs are dynamic and reversible processes that involve interactions between numerous enzymes and molecular components. Aberrant HMs are strongly associated with tumorigenesis and progression of breast cancer (BC), although the specific mechanisms are not completely understood. Moreover, there is no comprehensive overview of abnormal HMs in BC, and BC therapies that target HMs are still in their infancy. Therefore, this review summarizes the existing evidence regarding HMs that are involved in BC and the potential mechanisms that are related to aberrant HMs. Moreover, this review examines the currently available agents and approved drugs that have been tested in pre-clinical and clinical studies to evaluate their effects on HMs. Finally, this review covers the barriers to the clinical application of therapies that target HMs, and possible strategies that could help overcome these barriers and accelerate the use of these therapies to cure patients.
Collapse
Affiliation(s)
- Wei Li
- Harbin Medical University Third Hospital: Tumor Hospital of Harbin Medical University, Harbin, China
| | - Hao Wu
- Harbin Medical University Third Hospital: Tumor Hospital of Harbin Medical University, Harbin, China
| | - Shiyao Sui
- Harbin Medical University Third Hospital: Tumor Hospital of Harbin Medical University, Harbin, China
| | - Qin Wang
- Harbin Medical University Third Hospital: Tumor Hospital of Harbin Medical University, Harbin, China
| | - Shouping Xu
- Harbin Medical University Third Hospital: Tumor Hospital of Harbin Medical University, Harbin, China
| | - Da Pang
- Harbin Medical University Third Hospital: Tumor Hospital of Harbin Medical University, Harbin, China.,Heilongjiang Academy of Medical Sciences, Harbin, China
| |
Collapse
|
|
49
|
Sundarraj J, Taylor GC, von Kriegsheim A, Pradeepa MM. H3K36me3 and PSIP1/LEDGF associate with several DNA repair proteins, suggesting their role in efficient DNA repair at actively transcribing loci. Wellcome Open Res 2021; 2:83. [PMID: 34541330 PMCID: PMC8422350 DOI: 10.12688/wellcomeopenres.11589.4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/07/2021] [Indexed: 12/15/2022] Open
Abstract
Background: Trimethylation at histone H3 at lysine 36 (H3K36me3) is associated with expressed gene bodies and recruit proteins implicated in transcription, splicing and DNA repair. PC4 and SF2 interacting protein (PSIP1/LEDGF) is a transcriptional coactivator, possesses an H3K36me3 reader PWWP domain. Alternatively spliced isoforms of PSIP1 binds to H3K36me3 and suggested to function as adaptor proteins to recruit transcriptional modulators, splicing factors and proteins that promote homology-directed repair (HDR), to H3K36me3 chromatin. Methods: We performed chromatin immunoprecipitation of H3K36me3 followed by quantitative mass spectrometry (qMS) to identify proteins associated with H3K36 trimethylated chromatin in mouse embryonic stem cells (mESCs). We also performed stable isotope labelling with amino acids in cell culture (SILAC) followed by qMS for a longer isoform of PSIP1 (PSIP/p75) and MOF/KAT8 in mESCs and mouse embryonic fibroblasts ( MEFs). Furthermore, immunoprecipitation followed by western blotting was performed to validate the qMS data. DNA damage in PSIP1 knockout MEFs was assayed by a comet assay. Results: Proteomic analysis shows the association of proteins involved in transcriptional elongation, RNA processing and DNA repair with H3K36me3 chromatin. Furthermore, we show DNA repair proteins like PARP1, gamma H2A.X, XRCC1, DNA ligase 3, SPT16, Topoisomerases and BAZ1B are predominant interacting partners of PSIP /p75. We further validated the association of PSIP/p75 with PARP1, hnRNPU and gamma H2A.X and also demonstrated accumulation of damaged DNA in PSIP1 knockout MEFs. Conclusions: In contrast to the previously demonstrated role of H3K36me3 and PSIP/p75 in promoting homology-directed repair (HDR), our data support a wider role of H3K36me3 and PSIP1 in maintaining the genome integrity by recruiting proteins involved in DNA damage response pathways to the actively transcribed loci.
Collapse
Affiliation(s)
- Jayakumar Sundarraj
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK
- Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, 40085, India
| | - Gillian C.A. Taylor
- MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Alex von Kriegsheim
- MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Madapura M Pradeepa
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK
- MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK
- School of Biological Sciences, University of Essex, Colchester, CO4 3SQ, UK
| |
Collapse
|
|
50
|
Zeisig BB, So CWE. Therapeutic Opportunities of Targeting Canonical and Noncanonical PcG/TrxG Functions in Acute Myeloid Leukemia. Annu Rev Genomics Hum Genet 2021; 22:103-125. [PMID: 33929894 DOI: 10.1146/annurev-genom-111120-102443] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Transcriptional deregulation is a key driver of acute myeloid leukemia (AML), a heterogeneous blood cancer with poor survival rates. Polycomb group (PcG) and Trithorax group (TrxG) genes, originally identified in Drosophila melanogaster several decades ago as master regulators of cellular identity and epigenetic memory, not only are important in mammalian development but also play a key role in AML disease biology. In addition to their classical canonical antagonistic transcriptional functions, noncanonical synergistic and nontranscriptional functions of PcG and TrxG are emerging. Here, we review the biochemical properties of major mammalian PcG and TrxG complexes and their roles in AML disease biology, including disease maintenance as well as drug resistance. We summarize current efforts on targeting PcG and TrxG for treatment of AML and propose rational synthetic lethality and drug-induced antagonistic pleiotropy options involving PcG and TrxG as potential new therapeutic avenues for treatment of AML.
Collapse
Affiliation(s)
- Bernd B Zeisig
- Leukaemia and Stem Cell Biology Group, School of Cancer and Pharmaceutical Sciences, King's College London, London SE5 9NU, United Kingdom;
- Department of Haematological Medicine, King's College Hospital, London SE5 9RS, United Kingdom
| | - Chi Wai Eric So
- Leukaemia and Stem Cell Biology Group, School of Cancer and Pharmaceutical Sciences, King's College London, London SE5 9NU, United Kingdom;
- Department of Haematological Medicine, King's College Hospital, London SE5 9RS, United Kingdom
| |
Collapse
|