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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 DOI: 10.1038/s41467-025-59381-2] [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: 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.
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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.
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Zhang Y, Wang T, Wang Z, Shi X, Jin J. Functions and Therapeutic Potentials of Long Noncoding RNA in Skeletal Muscle Atrophy and Dystrophy. J Cachexia Sarcopenia Muscle 2025; 16:e13747. [PMID: 40034097 PMCID: PMC11876862 DOI: 10.1002/jcsm.13747] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 12/23/2024] [Accepted: 02/04/2025] [Indexed: 03/05/2025] Open
Abstract
Skeletal muscle is the most abundant tissue in the human body and is responsible for movement, metabolism, energy production and longevity. Muscle atrophy is a frequent complication of several diseases and occurs when protein degradation exceeds protein synthesis. Genetics, ageing, nerve injury, weightlessness, cancer, chronic diseases, the accumulation of metabolic byproducts and other stimuli can lead to muscle atrophy. Muscular dystrophy is a neuromuscular disorder, part of which is caused by the deficiency of dystrophin protein and is mostly related to genetics. Muscle atrophy and muscular dystrophy are accompanied by dynamic changes in transcriptomic, translational and epigenetic regulation. Multiple signalling pathways, such as the transforming growth factor-β (TGF-β) signalling pathway, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway, inflammatory signalling pathways, neuromechanical signalling pathways, endoplasmic reticulum stress and glucocorticoids signalling pathways, regulate muscle atrophy. A large number of long noncoding RNAs (lncRNAs) have been found to be abnormally expressed in atrophic muscles and dystrophic muscles and regulate the balance of muscle protein synthesis and degradation or dystrophin protein expression. These lncRNAs may serve as potential targets for treating muscle atrophy and muscular dystrophy. In this review, we summarized the known lncRNAs related to muscular dystrophy and muscle atrophy induced by denervation, ageing, weightlessness, cachexia and abnormal myogenesis, along with their molecular mechanisms. Finally, we explored the potential of using these lncRNAs as therapeutic targets for muscle atrophy and muscular dystrophy, including the methods of discovery and clinical application prospects for functional lncRNAs.
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Affiliation(s)
- Yidi Zhang
- Laboratory of Animal Fat Deposition and Muscle Development, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and TechnologyNorthwest A&F UniversityYanglingChina
| | - Teng Wang
- Laboratory of Animal Fat Deposition and Muscle Development, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and TechnologyNorthwest A&F UniversityYanglingChina
| | - Ziang Wang
- Laboratory of Animal Fat Deposition and Muscle Development, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and TechnologyNorthwest A&F UniversityYanglingChina
| | - Xin'e Shi
- Laboratory of Animal Fat Deposition and Muscle Development, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and TechnologyNorthwest A&F UniversityYanglingChina
| | - Jianjun Jin
- Laboratory of Animal Fat Deposition and Muscle Development, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and TechnologyNorthwest A&F UniversityYanglingChina
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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.
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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.
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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.
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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
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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.
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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
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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.
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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
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Han JY, Kim TY, Park J. Clinical and Genetic Characterization of Adolescent-Onset Epilepsy: A Single-Center Experience in Republic of Korea. Biomedicines 2024; 12:2663. [PMID: 39767570 PMCID: PMC11726859 DOI: 10.3390/biomedicines12122663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 11/18/2024] [Accepted: 11/20/2024] [Indexed: 01/16/2025] Open
Abstract
OBJECTIVES This study investigated the characteristics of adolescent-onset epilepsy (AOE) and conducted genetic tests on a cohort of 76 Korean patients to identify variants and expand the spectrum of mutations associated with AOE. METHODS Clinical exome sequencing after routine karyotyping and chromosomal microarray was performed to identify causative variants and expand the spectrum of mutations associated with AOE. RESULTS In cases of AOE without neurodevelopmental delay (NDD), this study identified four likely pathogenic variants (LPVs) or variants of uncertain significance (VUS) and two copy number variations (CNVs). To explore the unique features of AOE; clinical manifestations were compared between patients with and without NDD. The analysis revealed statistically significant differences in the prevalence of males and the yield of genetic testing results. AOE without NDD had a lower prevalence in males (49%) compared to AOE with NDD (60%) (p = 0.007). Genetic alterations: AOE with NDD exhibited a higher frequency of genetic alterations (35%) compared to AOE without NDD (12%) (p = 0.011). Thorough evaluation of AOE can be particularly challenging in adolescent patients. Some individuals may display genetic variations due to a phenomenon known as locus heterogeneity, where different genetic causes lead to similar clinical presentations. CONCLUSIONS Implementing a robust genetic workflow is crucial for accurately diagnosing AOE, even in cases with complex genetic underpinnings. This study underscores the importance of genetic testing as an essential diagnostic tool for AOE. Identifying genetic variants and understanding their clinical correlations can aid in improving diagnostic accuracy and optimizing treatment approaches for adolescent patients with epilepsy.
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Affiliation(s)
- Ji Yoon Han
- Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
| | - Tae Yun Kim
- Department of Thoracic and Cardiovascular Surgery, College of Medicine, Jeonbuk National University, Jeonju 54907, Republic of Korea;
| | - Joonhong Park
- Department of Laboratory Medicine, College of Medicine, Jeonbuk National University, Jeonju 54907, Republic of Korea
- Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Republic of Korea
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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.
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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
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9
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Zhang C, Liu W, Xu L, Liu S, Che F. Abnormal H3K4 enzyme catalytic activity and neuronal morphology caused by ASH1L mutations in individuals with Tourette syndrome. Eur Child Adolesc Psychiatry 2024; 33:3913-3923. [PMID: 38634863 DOI: 10.1007/s00787-024-02437-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Accepted: 04/04/2024] [Indexed: 04/19/2024]
Abstract
ASH1L potentially contributes to Tourette syndrome (TS) and other neuropsychiatric disorders, as our previous studies have shown. It regulates essential developmental genes by counteracting polycomb-mediated transcriptional repression, which restricts chromatin accessibility at target genes. ASH1L is highly expressed in the adult brain, playing a crucial role in the early stage. However, it remains unclear how ASH1L mutations carried by patients with TS participate in regulating neuronal growth processes leading to TS traits. Five TS families recruited in our study underwent comprehensive physical examinations and questionnaires to record clinical phenotypes and environmental impact factors. We validated the variants via Sanger sequencing and constructed two mutants near the catalytic domain of ASH1L. We conducted molecular modeling, in vitro assays, and primary neuron cultures to find the role of ASH1L in neuronal development and its correlation with TS. In this study, we validated five pathogenic ASH1L rare variants and observed symptoms in patients with simple tics and behavioral comorbidities. Mutations near the catalytic domain of TS patients cause mental state abnormalities and disrupt ASH1L function by destabilizing its spatial conformation, leading to decreased activity of catalytic H3K4, thereby affecting the neurite growth. We need to conduct larger-scale studies on TS patients and perform additional neurological evaluations on mature neurons. We first reported the effects of ASH1L mutations in TS patients, including phenotypic heterogeneity, protein function, and neurological growth. This information contributes to understanding the neurodevelopmental pathogenesis of TS in patients with ASH1L mutations.
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Affiliation(s)
- Cheng Zhang
- Department of Neurology, The Second Affiliated Hospital of Shandong University, Jinan, 250033, Shandong, China
- Department of Neurology, Linyi People's Hospital, 27 East Section of Jiefang Road Lanshan District, Linyi, 276000, Shandong, China
| | - Wenmiao Liu
- Medical Genetic Department, The Affiliated Hospital of Qingdao University, Qingdao, 266003, Shandong, China
| | - Lulu Xu
- Medical Genetic Department, The Affiliated Hospital of Qingdao University, Qingdao, 266003, Shandong, China
| | - Shiguo Liu
- Medical Genetic Department, The Affiliated Hospital of Qingdao University, Qingdao, 266003, Shandong, China.
| | - Fengyuan Che
- Department of Neurology, Linyi People's Hospital, 27 East Section of Jiefang Road Lanshan District, Linyi, 276000, Shandong, China
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10
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Pollock TA, Margetts AV, Vilca SJ, Tuesta LM. Cocaine taking and craving produce distinct transcriptional profiles in dopamine neurons. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.11.617923. [PMID: 39416214 PMCID: PMC11482921 DOI: 10.1101/2024.10.11.617923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/19/2024]
Abstract
Dopamine (DA) signaling plays an essential role in reward valence attribution and in encoding the reinforcing properties of natural and artificial rewards. The adaptive responses from midbrain dopamine neurons to artificial rewards such as drugs of abuse are therefore important for understanding the development of substance use disorders. Drug-induced changes in gene expression are one such adaptation that can determine the activity of dopamine signaling in projection regions of the brain reward system. One of the major challenges to obtaining this understanding involves the complex cellular makeup of the brain, where each neuron population can be defined by a distinct transcriptional profile. To bridge this gap, we have adapted a virus-based method for labeling and capture of dopamine nuclei, coupled with nuclear RNA-sequencing, to study the transcriptional adaptations, specifically, of dopamine neurons in the ventral tegmental area (VTA) during cocaine taking and cocaine craving, using a mouse model of cocaine intravenous self-administration (IVSA). Our results show significant changes in gene expression across non-drug operant training, cocaine taking, and cocaine craving, highlighted by an enrichment of repressive epigenetic modifying enzyme gene expression during cocaine craving. Immunohistochemical validation further revealed an increase of H3K9me3 deposition in DA neurons during cocaine craving. These results demonstrate that cocaine-induced transcriptional adaptations in dopamine neurons vary by phase of self-administration and underscore the utility of this approach for identifying relevant phase-specific molecular targets to study the behavioral course of substance use disorders.
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Affiliation(s)
- Tate A. Pollock
- Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL 33136
- Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, FL 33136
| | - Alexander V. Margetts
- Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL 33136
- Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, FL 33136
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136
| | - Samara J. Vilca
- Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL 33136
- Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, FL 33136
| | - Luis M. Tuesta
- Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL 33136
- Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, FL 33136
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136
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11
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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.
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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
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12
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Ma S, Long G, Jiang Z, Zhang Y, Sun L, Pan Y, You Q, Guo X. Recent advances in targeting histone H3 lysine 36 methyltransferases for cancer therapy. Eur J Med Chem 2024; 274:116532. [PMID: 38805937 DOI: 10.1016/j.ejmech.2024.116532] [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: 04/09/2024] [Revised: 05/14/2024] [Accepted: 05/22/2024] [Indexed: 05/30/2024]
Abstract
Histone H3 lysine 36 (H3K36) methylation is a typical epigenetic histone modification that is involved in various biological processes such as DNA transcription, repair and recombination in vivo. Mutations, translocations, and aberrant gene expression associated with H3K36 methyltransferases have been implicated in different malignancies such as acute myeloid leukemia, lung cancer, multiple myeloma, and others. Herein, we provided a comprehensive overview of the latest advances in small molecule inhibitors targeting H3K36 methyltransferases. We analyzed the structures and biological functions of the H3K36 methyltransferases family members. Additionally, we discussed the potential directions for future development of inhibitors targeting H3K36 methyltransferases.
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Affiliation(s)
- Sai Ma
- Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Guanlu Long
- Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Zheng Jiang
- Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Yan Zhang
- Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Liangkui Sun
- Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Yun Pan
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Qidong You
- Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
| | - Xiaoke Guo
- Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
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13
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Ju J, Li Y, Ling P, Luo J, Wei W, Yuan W, Wang C, Su J. H3K36 methyltransferase GhKMT3;1a and GhKMT3;2a promote flowering in upland cotton. BMC PLANT BIOLOGY 2024; 24:739. [PMID: 39095699 PMCID: PMC11295449 DOI: 10.1186/s12870-024-05457-y] [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: 10/20/2023] [Accepted: 07/25/2024] [Indexed: 08/04/2024]
Abstract
BACKGROUND The SET domain group (SDG) genes encode histone lysine methyltransferases, which regulate gene transcription by altering chromatin structure and play pivotal roles in plant flowering determination. However, few studies have investigated their role in the regulation of flowering in upland cotton. RESULTS A total of 86 SDG genes were identified through genome-wide analysis in upland cotton (Gossypium hirsutum). These genes were unevenly distributed across 25 chromosomes. Cluster analysis revealed that the 86 GhSDGs were divided into seven main branches. RNA-seq data and qRT‒PCR analysis revealed that lysine methyltransferase 3 (KMT3) genes were expressed at high levels in stamens, pistils and other floral organs. Using virus-induced gene silencing (VIGS), functional characterization of GhKMT3;1a and GhKMT3;2a revealed that, compared with those of the controls, the GhKMT3;1a- and GhKMT3;2a-silenced plants exhibited later budding and flowering and lower plant heightwere shorter. In addition, the expression of flowering-related genes (GhAP1, GhSOC1 and GhFT) significantly decreased and the expression level of GhSVP significantly increased in the GhKMT3;1a- and GhKMT3;2a-silenced plants compared with the control plants. CONCLUSION A total of 86 SDG genes were identified in upland cotton, among which GhKMT3;1a and GhKMT3;2a might regulate flowering by affecting the expression of GhAP1, GhSOC1, GhFT and GhSVP. These findings will provide genetic resources for advanced molecular breeding in the future.
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Affiliation(s)
- Jisheng Ju
- College of Life Science and Technology, Gansu Agricultural University, Lanzhou, 730070, China
| | - Ying Li
- College of Life Science and Technology, Gansu Agricultural University, Lanzhou, 730070, China
| | - Pingjie Ling
- College of Life Science and Technology, Gansu Agricultural University, Lanzhou, 730070, China
| | - Jin Luo
- College of Life Science and Technology, Gansu Agricultural University, Lanzhou, 730070, China
| | - Wei Wei
- College of Life Science and Technology, Gansu Agricultural University, Lanzhou, 730070, China
| | - Wenmin Yuan
- College of Life Science and Technology, Gansu Agricultural University, Lanzhou, 730070, China
| | - Caixiang Wang
- College of Life Science and Technology, Gansu Agricultural University, Lanzhou, 730070, China.
| | - Junji Su
- College of Life Science and Technology, Gansu Agricultural University, Lanzhou, 730070, China.
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14
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Cordova I, Blesson A, Savatt JM, Sveden A, Mahida S, Hazlett H, Rooney Riggs E, Chopra M. Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental Disorder. Genes (Basel) 2024; 15:423. [PMID: 38674358 PMCID: PMC11049257 DOI: 10.3390/genes15040423] [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: 02/15/2024] [Revised: 03/21/2024] [Accepted: 03/22/2024] [Indexed: 04/28/2024] Open
Abstract
Pathogenic ASH1L variants have been reported in probands with broad phenotypic presentations, including intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, seizures, congenital anomalies, and other skeletal, muscular, and sleep differences. Here, we review previously published individuals with pathogenic ASH1L variants and report three further probands with novel ASH1L variants and previously unreported phenotypic features, including mixed receptive language disorder and gait disturbances. These novel data from the Brain Gene Registry, an accessible repository of clinically derived genotypic and phenotypic data, have allowed for the expansion of the phenotypic and genotypic spectrum of this condition.
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Affiliation(s)
- Ineke Cordova
- Autism and Developmental Medicine Institute, Geisinger, Danville, PA 17822, USA; (I.C.); (E.R.R.)
| | - Alyssa Blesson
- Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD 21205, USA
| | - Juliann M. Savatt
- Autism and Developmental Medicine Institute, Geisinger, Danville, PA 17822, USA; (I.C.); (E.R.R.)
| | - Abigail Sveden
- Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Sonal Mahida
- Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Heather Hazlett
- Department of Psychiatry, University of North Carolina Intellectual and Developmental Disability Research Center, Chapel Hill, NC 27510, USA
| | - Erin Rooney Riggs
- Autism and Developmental Medicine Institute, Geisinger, Danville, PA 17822, USA; (I.C.); (E.R.R.)
| | - Maya Chopra
- Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Boston, MA 02115, USA
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15
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Zhao Y, Skovgaard Z, Wang Q. Regulation of adipogenesis by histone methyltransferases. Differentiation 2024; 136:100746. [PMID: 38241884 DOI: 10.1016/j.diff.2024.100746] [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: 07/19/2023] [Revised: 12/15/2023] [Accepted: 01/12/2024] [Indexed: 01/21/2024]
Abstract
Epigenetic regulation is a critical component of lineage determination. Adipogenesis is the process through which uncommitted stem cells or adipogenic precursor cells differentiate into adipocytes, the most abundant cell type of the adipose tissue. Studies examining chromatin modification during adipogenesis have provided further understanding of the molecular blueprint that controls the onset of adipogenic differentiation. Unlike histone acetylation, histone methylation has context dependent effects on the activity of a transcribed region of DNA, with individual or combined marks on different histone residues providing distinct signals for gene expression. Over half of the 42 histone methyltransferases identified in mammalian cells have been investigated in their role during adipogenesis, but across the large body of literature available, there is a lack of clarity over potential correlations or emerging patterns among the different players. In this review, we will summarize important findings from studies published in the past 15 years that have investigated the role of histone methyltransferases during adipogenesis, including both protein arginine methyltransferases (PRMTs) and lysine methyltransferases (KMTs). We further reveal that PRMT1/4/5, H3K4 KMTs (MLL1, MLL3, MLL4, SMYD2 and SET7/9) and H3K27 KMTs (EZH2) all play positive roles during adipogenesis, while PRMT6/7 and H3K9 KMTs (G9a, SUV39H1, SUV39H2, and SETDB1) play negative roles during adipogenesis.
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Affiliation(s)
| | | | - Qinyi Wang
- Computer Science Department, California State Polytechnic University Pomona, USA
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16
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Schnee P, Pleiss J, Jeltsch A. Approaching the catalytic mechanism of protein lysine methyltransferases by biochemical and simulation techniques. Crit Rev Biochem Mol Biol 2024; 59:20-68. [PMID: 38449437 DOI: 10.1080/10409238.2024.2318547] [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: 10/24/2023] [Accepted: 02/10/2024] [Indexed: 03/08/2024]
Abstract
Protein lysine methyltransferases (PKMTs) transfer up to three methyl groups to the side chains of lysine residues in proteins and fulfill important regulatory functions by controlling protein stability, localization and protein/protein interactions. The methylation reactions are highly regulated, and aberrant methylation of proteins is associated with several types of diseases including neurologic disorders, cardiovascular diseases, and various types of cancer. This review describes novel insights into the catalytic machinery of various PKMTs achieved by the combined application of biochemical experiments and simulation approaches during the last years, focusing on clinically relevant and well-studied enzymes of this group like DOT1L, SMYD1-3, SET7/9, G9a/GLP, SETD2, SUV420H2, NSD1/2, different MLLs and EZH2. Biochemical experiments have unraveled many mechanistic features of PKMTs concerning their substrate and product specificity, processivity and the effects of somatic mutations observed in PKMTs in cancer cells. Structural data additionally provided information about the substrate recognition, enzyme-substrate complex formation, and allowed for simulations of the substrate peptide interaction and mechanism of PKMTs with atomistic resolution by molecular dynamics and hybrid quantum mechanics/molecular mechanics methods. These simulation technologies uncovered important mechanistic details of the PKMT reaction mechanism including the processes responsible for the deprotonation of the target lysine residue, essential conformational changes of the PKMT upon substrate binding, but also rationalized regulatory principles like PKMT autoinhibition. Further developments are discussed that could bring us closer to a mechanistic understanding of catalysis of this important class of enzymes in the near future. The results described here illustrate the power of the investigation of enzyme mechanisms by the combined application of biochemical experiments and simulation technologies.
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Affiliation(s)
- Philipp Schnee
- Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Stuttgart, Germany
| | - Jürgen Pleiss
- Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Stuttgart, Germany
| | - Albert Jeltsch
- Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Stuttgart, Germany
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17
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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.
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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.
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18
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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.
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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.
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19
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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.
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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.
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20
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Roth C, Kilpinen H, Kurian MA, Barral S. Histone lysine methyltransferase-related neurodevelopmental disorders: current knowledge and saRNA future therapies. Front Cell Dev Biol 2023; 11:1090046. [PMID: 36923252 PMCID: PMC10009263 DOI: 10.3389/fcell.2023.1090046] [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: 12/07/2022] [Accepted: 02/06/2023] [Indexed: 03/02/2023] Open
Abstract
Neurodevelopmental disorders encompass a group of debilitating diseases presenting with motor and cognitive dysfunction, with variable age of onset and disease severity. Advances in genetic diagnostic tools have facilitated the identification of several monogenic chromatin remodeling diseases that cause Neurodevelopmental disorders. Chromatin remodelers play a key role in the neuro-epigenetic landscape and regulation of brain development; it is therefore not surprising that mutations, leading to loss of protein function, result in aberrant neurodevelopment. Heterozygous, usually de novo mutations in histone lysine methyltransferases have been described in patients leading to haploinsufficiency, dysregulated protein levels and impaired protein function. Studies in animal models and patient-derived cell lines, have highlighted the role of histone lysine methyltransferases in the regulation of cell self-renewal, cell fate specification and apoptosis. To date, in depth studies of histone lysine methyltransferases in oncology have provided strong evidence of histone lysine methyltransferase dysregulation as a determinant of cancer progression and drug resistance. As a result, histone lysine methyltransferases have become an important therapeutic target for the treatment of different cancer forms. Despite recent advances, we still lack knowledge about the role of histone lysine methyltransferases in neuronal development. This has hampered both the study and development of precision therapies for histone lysine methyltransferases-related Neurodevelopmental disorders. In this review, we will discuss the current knowledge of the role of histone lysine methyltransferases in neuronal development and disease progression. We will also discuss how RNA-based technologies using small-activating RNAs could potentially provide a novel therapeutic approach for the future treatment of histone lysine methyltransferase haploinsufficiency in these Neurodevelopmental disorders, and how they could be first tested in state-of-the-art patient-derived neuronal models.
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Affiliation(s)
- Charlotte Roth
- Molecular Neurosciences, Developmental Neurosciences Programme, Zayed Centre for Research into Rare Disease in Children, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
| | - Helena Kilpinen
- Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
- Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Manju A. Kurian
- Molecular Neurosciences, Developmental Neurosciences Programme, Zayed Centre for Research into Rare Disease in Children, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
- Department of Neurology, Great Ormond Street Hospital for Children, London, United Kingdom
| | - Serena Barral
- Molecular Neurosciences, Developmental Neurosciences Programme, Zayed Centre for Research into Rare Disease in Children, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
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21
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Sharda A, Humphrey TC. The role of histone H3K36me3 writers, readers and erasers in maintaining genome stability. DNA Repair (Amst) 2022; 119:103407. [PMID: 36155242 DOI: 10.1016/j.dnarep.2022.103407] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 09/15/2022] [Accepted: 09/15/2022] [Indexed: 11/03/2022]
Abstract
Histone Post-Translational Modifications (PTMs) play fundamental roles in mediating DNA-related processes such as transcription, replication and repair. The histone mark H3K36me3 and its associated methyltransferase SETD2 (Set2 in yeast) are archetypical in this regard, performing critical roles in each of these DNA transactions. Here, we present an overview of H3K36me3 regulation and the roles of its writers, readers and erasers in maintaining genome stability through facilitating DNA double-strand break (DSB) repair, checkpoint signalling and replication stress responses. Further, we consider how loss of SETD2 and H3K36me3, frequently observed in a number of different cancer types, can be specifically targeted in the clinic through exploiting loss of particular genome stability functions.
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Affiliation(s)
- Asmita Sharda
- CRUK and MRC Oxford Institute for Radiation Oncology, Old Road Campus Research Building, University of Oxford, Oxford OX3 7DQ, UK
| | - Timothy C Humphrey
- CRUK and MRC Oxford Institute for Radiation Oncology, Old Road Campus Research Building, University of Oxford, Oxford OX3 7DQ, UK
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22
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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.
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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.
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23
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Ma Q, Song C, Yin B, Shi Y, Ye L. The role of Trithorax family regulating osteogenic and Chondrogenic differentiation in mesenchymal stem cells. Cell Prolif 2022; 55:e13233. [PMID: 35481717 PMCID: PMC9136489 DOI: 10.1111/cpr.13233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/17/2022] [Accepted: 03/28/2022] [Indexed: 02/05/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) hold great promise and clinical efficacy in bone/cartilage regeneration. With a deeper understanding of stem cell biology over the past decade, epigenetics stands out as one of the most promising ways to control MSCs differentiation. Trithorax group (TrxG) proteins, including the COMPASS family, ASH1L, CBP/p300 as histone modifying factors, and the SWI/SNF complexes as chromatin remodelers, play an important role in gene expression regulation during the process of stem cell differentiation. This review summarises the components and functions of TrxG complexes. We provide an overview of the regulation mechanisms of TrxG in MSCs osteogenic and chondrogenic differentiation, and discuss the prospects of epigenetic regulation mediated by TrxG in bone and cartilage regeneration.
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Affiliation(s)
- Qingge Ma
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Chenghao Song
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Bei Yin
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yu Shi
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ling Ye
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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24
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Feoli A, Viviano M, Cipriano A, Milite C, Castellano S, Sbardella G. Lysine methyltransferase inhibitors: where we are now. RSC Chem Biol 2022; 3:359-406. [PMID: 35441141 PMCID: PMC8985178 DOI: 10.1039/d1cb00196e] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 12/10/2021] [Indexed: 12/14/2022] Open
Abstract
Protein lysine methyltransferases constitute a large family of epigenetic writers that catalyse the transfer of a methyl group from the cofactor S-adenosyl-l-methionine to histone- and non-histone-specific substrates. Alterations in the expression and activity of these proteins have been linked to the genesis and progress of several diseases, including cancer, neurological disorders, and growing defects, hence they represent interesting targets for new therapeutic approaches. Over the past two decades, the identification of modulators of lysine methyltransferases has increased tremendously, clarifying the role of these proteins in different physio-pathological states. The aim of this review is to furnish an updated outlook about the protein lysine methyltransferases disclosed modulators, reporting their potency, their mechanism of action and their eventual use in clinical and preclinical studies.
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Affiliation(s)
- Alessandra Feoli
- Department of Pharmacy, Epigenetic Med Chem Lab, University of Salerno via Giovanni Paolo II 132 I-84084 Fisciano SA Italy +39-089-96-9602 +39-089-96-9770
| | - Monica Viviano
- Department of Pharmacy, Epigenetic Med Chem Lab, University of Salerno via Giovanni Paolo II 132 I-84084 Fisciano SA Italy +39-089-96-9602 +39-089-96-9770
| | - Alessandra Cipriano
- Department of Pharmacy, Epigenetic Med Chem Lab, University of Salerno via Giovanni Paolo II 132 I-84084 Fisciano SA Italy +39-089-96-9602 +39-089-96-9770
| | - Ciro Milite
- Department of Pharmacy, Epigenetic Med Chem Lab, University of Salerno via Giovanni Paolo II 132 I-84084 Fisciano SA Italy +39-089-96-9602 +39-089-96-9770
| | - Sabrina Castellano
- Department of Pharmacy, Epigenetic Med Chem Lab, University of Salerno via Giovanni Paolo II 132 I-84084 Fisciano SA Italy +39-089-96-9602 +39-089-96-9770
| | - Gianluca Sbardella
- Department of Pharmacy, Epigenetic Med Chem Lab, University of Salerno via Giovanni Paolo II 132 I-84084 Fisciano SA Italy +39-089-96-9602 +39-089-96-9770
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25
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Abstract
The functions, purposes, and roles of metallothioneins have been the subject of speculations since the discovery of the protein over 60 years ago. This article guides through the history of investigations and resolves multiple contentions by providing new interpretations of the structure-stability-function relationship. It challenges the dogma that the biologically relevant structure of the mammalian proteins is only the one determined by X-ray diffraction and NMR spectroscopy. The terms metallothionein and thionein are ambiguous and insufficient to understand biological function. The proteins need to be seen in their biological context, which limits and defines the chemistry possible. They exist in multiple forms with different degrees of metalation and types of metal ions. The homoleptic thiolate coordination of mammalian metallothioneins is important for their molecular mechanism. It endows the proteins with redox activity and a specific pH dependence of their metal affinities. The proteins, therefore, also exist in different redox states of the sulfur donor ligands. Their coordination dynamics allows a vast conformational landscape for interactions with other proteins and ligands. Many fundamental signal transduction pathways regulate the expression of the dozen of human metallothionein genes. Recent advances in understanding the control of cellular zinc and copper homeostasis are the foundation for suggesting that mammalian metallothioneins provide a highly dynamic, regulated, and uniquely biological metal buffer to control the availability, fluctuations, and signaling transients of the most competitive Zn(II) and Cu(I) ions in cellular space and time.
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Affiliation(s)
- Artur Krężel
- Department of Chemical Biology, Faculty of Biotechnology, University of Wrocław, Wrocław 50-383, Poland
| | - Wolfgang Maret
- Departments of Biochemistry and Nutritional Sciences, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 9NH, U.K
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26
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Tellier M. Structure, Activity, and Function of SETMAR Protein Lysine Methyltransferase. Life (Basel) 2021; 11:life11121342. [PMID: 34947873 PMCID: PMC8704517 DOI: 10.3390/life11121342] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 11/30/2021] [Accepted: 12/01/2021] [Indexed: 12/21/2022] Open
Abstract
SETMAR is a protein lysine methyltransferase that is involved in several DNA processes, including DNA repair via the non-homologous end joining (NHEJ) pathway, regulation of gene expression, illegitimate DNA integration, and DNA decatenation. However, SETMAR is an atypical protein lysine methyltransferase since in anthropoid primates, the SET domain is fused to an inactive DNA transposase. The presence of the DNA transposase domain confers to SETMAR a DNA binding activity towards the remnants of its transposable element, which has resulted in the emergence of a gene regulatory function. Both the SET and the DNA transposase domains are involved in the different cellular roles of SETMAR, indicating the presence of novel and specific functions in anthropoid primates. In addition, SETMAR is dysregulated in different types of cancer, indicating a potential pathological role. While some light has been shed on SETMAR functions, more research and new tools are needed to better understand the cellular activities of SETMAR and to investigate the therapeutic potential of SETMAR.
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Affiliation(s)
- Michael Tellier
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK
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27
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Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures. Nat Commun 2021; 12:6589. [PMID: 34782621 PMCID: PMC8593046 DOI: 10.1038/s41467-021-26972-8] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 10/29/2021] [Indexed: 12/30/2022] Open
Abstract
ASH1L, a histone methyltransferase, is identified as a top-ranking risk factor for autism spectrum disorder (ASD), however, little is known about the biological mechanisms underlying the link of ASH1L haploinsufficiency to ASD. Here we show that ASH1L expression and H3K4me3 level are significantly decreased in the prefrontal cortex (PFC) of postmortem tissues from ASD patients. Knockdown of Ash1L in PFC of juvenile mice induces the downregulation of risk genes associated with ASD, intellectual disability (ID) and epilepsy. These downregulated genes are enriched in excitatory and inhibitory synaptic function and have decreased H3K4me3 occupancy at their promoters. Furthermore, Ash1L deficiency in PFC causes the diminished GABAergic inhibition, enhanced glutamatergic transmission, and elevated PFC pyramidal neuronal excitability, which is associated with severe seizures and early mortality. Chemogenetic inhibition of PFC pyramidal neuronal activity, combined with the administration of GABA enhancer diazepam, rescues PFC synaptic imbalance and seizures, but not autistic social deficits or anxiety-like behaviors. These results have revealed the critical role of ASH1L in regulating synaptic gene expression and seizures, which provides insights into treatment strategies for ASH1L-associated brain diseases.
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28
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An update on allosteric modulators as a promising strategy targeting histone methyltransferase. Pharmacol Res 2021; 172:105865. [PMID: 34474102 DOI: 10.1016/j.phrs.2021.105865] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/22/2021] [Accepted: 08/27/2021] [Indexed: 02/07/2023]
Abstract
Histone methylation is a vital post-translational modification process in epigenetic regulation. The perturbation of histone methylation accounts for many diseases, including malignant cancers. Although achieving significant advances over past decades, orthosteric inhibitors targeting histone methyltransferases still suffer from challenges on subtype selectivity and acquired drug-resistant mutations. As an alternative, new compounds targeting the evolutionarily less conserved allosteric sites, exemplified by HKMTs and PRMTs inhibitors, offer a promising strategy to address this quandary. Herein, we highlight the allosteric sites and mechanisms in histone methyltransferases along with representative allosteric modulators, expecting to facilitate the discovery of allosteric modulators in favor of epigenetic therapy.
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29
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Liu H, Liu DT, Lan S, Yang Y, Huang J, Huang J, Fang L. ASH1L mutation caused seizures and intellectual disability in twin sisters. J Clin Neurosci 2021; 91:69-74. [PMID: 34373061 DOI: 10.1016/j.jocn.2021.06.038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 03/23/2021] [Accepted: 06/20/2021] [Indexed: 11/18/2022]
Abstract
ASH1L mutations have been identified with variable phenotypes, including intellectual disability, autism spectrum disorder (ASD), and multiple congenital anomalies (MCA). However, the mechanisms underlying this phenotypic variation remain unknown. Here, we present twin sisters exhibiting mild intellectual disability and seizures. Whole-exome sequencing of the family revealed a novel de novo heterozygous sequence variant, NM_018489.2: c.2678dup (p.Lys894*) in exon 3 of ASH1L which was estimated to be pathogenic. Furthermore, we reviewed previously reported ASH1L mutations in order to evaluate genotype-phenotype correlations for ASH1L variants. We found that patients with missense mutations in ASH1L appeared to present with more severe phenotypes and a higher likelihood of ASD than those with truncating mutations. The relationship between phenotype and genotype reported across several patients may help to explain the mechanisms underlying the phenotypic variation commonly observed between ASH1L mutations.
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Affiliation(s)
- Hailing Liu
- Department of Neurology, Maoming People's Hospital, Maoming, Guangdong, China.
| | - De-Tian Liu
- Department of Neurology, Longgang District Central Hospital of Shenzhen, Guangdong, China
| | - Song Lan
- Department of Neurology, Maoming People's Hospital, Maoming, Guangdong, China.
| | - Yan Yang
- Department of Neurology, Maoming People's Hospital, Maoming, Guangdong, China
| | - Jingjing Huang
- Department of Neurology, Maoming People's Hospital, Maoming, Guangdong, China
| | - Jinbo Huang
- Department of Neurology, Maoming People's Hospital, Maoming, Guangdong, China
| | - Ling Fang
- Department of Neurology, Maoming People's Hospital, Maoming, Guangdong, China
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30
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Depletion of H3K36me2 recapitulates epigenomic and phenotypic changes induced by the H3.3K36M oncohistone mutation. Proc Natl Acad Sci U S A 2021; 118:2021795118. [PMID: 33619101 DOI: 10.1073/pnas.2021795118] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Hotspot histone H3 mutations have emerged as drivers of oncogenesis in cancers of multiple lineages. Specifically, H3 lysine 36 to methionine (H3K36M) mutations are recurrently identified in chondroblastomas, undifferentiated sarcomas, and head and neck cancers. While the mutation reduces global levels of both H3K36 dimethylation (H3K36me2) and trimethylation (H3K36me3) by dominantly inhibiting their respective specific methyltransferases, the relative contribution of these methylation states to the chromatin and phenotypic changes associated with H3K36M remains unclear. Here, we specifically deplete H3K36me2 or H3K36me3 in mesenchymal cells, using CRISPR-Cas9 to separately knock out the corresponding methyltransferases NSD1/2 or SETD2. By profiling and comparing the epigenomic and transcriptomic landscapes of these cells with cells expressing the H3.3K36M oncohistone, we find that the loss of H3K36me2 could largely recapitulate H3.3K36M's effect on redistribution of H3K27 trimethylation (H3K27me3) and gene expression. Consistently, knockout of Nsd1/2, but not Setd2, phenocopies the differentiation blockade and hypersensitivity to the DNA-hypomethylating agent induced by H3K36M. Together, our results support a functional divergence between H3K36me2 and H3K36me3 and their nonredundant roles in H3K36M-driven oncogenesis.
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31
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The Trithorax group protein ASH1 requires a combination of BAH domain and AT hooks, but not the SET domain, for mitotic chromatin binding and survival. Chromosoma 2021; 130:215-234. [PMID: 34331109 PMCID: PMC8426247 DOI: 10.1007/s00412-021-00762-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 07/03/2021] [Accepted: 07/06/2021] [Indexed: 11/20/2022]
Abstract
The Drosophila Trithorax group (TrxG) protein ASH1 remains associated with mitotic chromatin through mechanisms that are poorly understood. ASH1 dimethylates histone H3 at lysine 36 via its SET domain. Here, we identify domains of the TrxG protein ASH1 that are required for mitotic chromatin attachment in living Drosophila. Quantitative live imaging demonstrates that ASH1 requires AT hooks and the BAH domain but not the SET domain for full chromatin binding in metaphase, and that none of these domains are essential for interphase binding. Genetic experiments show that disruptions of the AT hooks and the BAH domain together, but not deletion of the SET domain alone, are lethal. Transcriptional profiling demonstrates that intact ASH1 AT hooks and the BAH domain are required to maintain expression levels of a specific set of genes, including several involved in cell identity and survival. This study identifies in vivo roles for specific ASH1 domains in mitotic binding, gene regulation, and survival that are distinct from its functions as a histone methyltransferase.
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32
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Jacobs NR, Norton PA. Role of chromosome 1q copy number variation in hepatocellular carcinoma. World J Hepatol 2021; 13:662-672. [PMID: 34239701 PMCID: PMC8239492 DOI: 10.4254/wjh.v13.i6.662] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 05/13/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Chromosome 1q often has been observed to be amplified in hepatocellular carcinoma. This review summarizes literature reports of multiple genes that have been proposed as possible 1q amplification drivers. These largely fall within 1q21-1q23. In addition, publicly available copy number alteration data from The Cancer Genome Atlas project were used to identify additional candidate genes involved in carcinogenesis. The most frequent location for gene amplification was 1q22, consistent with the results of the literature search. The genes TPM3 and NUF2 were found to be candidates whose amplification and/or mRNA up-regulation was most highly associated with poorer hepatocellular carcinoma outcomes.
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Affiliation(s)
- Nathan R Jacobs
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102, United States
| | - Pamela A Norton
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102, United States
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33
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Davidovich C, Zhang Q. Allosteric regulation of histone lysine methyltransferases: from context-specific regulation to selective drugs. Biochem Soc Trans 2021; 49:591-607. [PMID: 33769454 PMCID: PMC8106495 DOI: 10.1042/bst20200238] [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: 01/19/2021] [Revised: 03/02/2021] [Accepted: 03/03/2021] [Indexed: 02/06/2023]
Abstract
Histone lysine methyltransferases (HKMTs) are key regulators of many cellular processes. By definition, HKMTs catalyse the methylation of lysine residues in histone proteins. The enzymatic activities of HKMTs are under precise control, with their allosteric regulation emerging as a prevalent paradigm. We review the molecular mechanisms of allosteric regulation of HKMTs using well-studied histone H3 (K4, K9, K27 and K36) methyltransferases as examples. We discuss the current advances and future potential in targeting allosteric sites of HKMTs for drug development.
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Affiliation(s)
- Chen Davidovich
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
- EMBL-Australia and the ARC Centre of Excellence in Advanced Molecular Imaging, Clayton, Victoria, Australia
| | - Qi Zhang
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
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Li W, Yan J, Wang S, Wang Q, Wang C, Li Z, Zhang D, Ma F, Guan Q, Xu J. Genome-wide analysis of SET-domain group histone methyltransferases in apple reveals their role in development and stress responses. BMC Genomics 2021; 22:283. [PMID: 33874904 PMCID: PMC8054418 DOI: 10.1186/s12864-021-07596-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 04/09/2021] [Indexed: 12/13/2022] Open
Abstract
Background Histone lysine methylation plays an important role in plant development and stress responses by activating or repressing gene expression. Histone lysine methylation is catalyzed by a class of SET-domain group proteins (SDGs). Although an increasing number of studies have shown that SDGs play important regulatory roles in development and stress responses, the functions of SDGs in apple remain unclear. Results A total of 67 SDG members were identified in the Malus×domestica genome. Syntenic analysis revealed that most of the MdSDG duplicated gene pairs were associated with a recent genome-wide duplication event of the apple genome. These 67 MdSDG members were grouped into six classes based on sequence similarity and the findings of previous studies. The domain organization of each MdSDG class was characterized by specific patterns, which was consistent with the classification results. The tissue-specific expression patterns of MdSDGs among the 72 apple tissues in the different apple developmental stages were characterized to provide insight into their potential functions in development. The expression profiles of MdSDGs were also investigated in fruit development, the breaking of bud dormancy, and responses to abiotic and biotic stress; the results indicated that MdSDGs might play a regulatory role in development and stress responses. The subcellular localization and putative interaction network of MdSDG proteins were also analyzed. Conclusions This work presents a fundamental comprehensive analysis of SDG histone methyltransferases in apple and provides a basis for future studies of MdSDGs involved in apple development and stress responses. Supplementary Information The online version contains supplementary material available at 10.1186/s12864-021-07596-0.
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Affiliation(s)
- Wenjie Li
- State Key Laboratory of Crop Stress Biology for Arid Areas/Shaanxi Key Laboratory of Apple, College of Horticulture, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Jinjiao Yan
- College of Forestry, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Shicong Wang
- State Key Laboratory of Crop Stress Biology for Arid Areas/Shaanxi Key Laboratory of Apple, College of Horticulture, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Qianying Wang
- State Key Laboratory of Crop Stress Biology for Arid Areas/Shaanxi Key Laboratory of Apple, College of Horticulture, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Caixia Wang
- State Key Laboratory of Crop Stress Biology for Arid Areas/Shaanxi Key Laboratory of Apple, College of Horticulture, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Zhongxing Li
- State Key Laboratory of Crop Stress Biology for Arid Areas/Shaanxi Key Laboratory of Apple, College of Horticulture, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Dehui Zhang
- State Key Laboratory of Crop Stress Biology for Arid Areas/Shaanxi Key Laboratory of Apple, College of Horticulture, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Fengwang Ma
- State Key Laboratory of Crop Stress Biology for Arid Areas/Shaanxi Key Laboratory of Apple, College of Horticulture, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Qingmei Guan
- State Key Laboratory of Crop Stress Biology for Arid Areas/Shaanxi Key Laboratory of Apple, College of Horticulture, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Jidi Xu
- State Key Laboratory of Crop Stress Biology for Arid Areas/Shaanxi Key Laboratory of Apple, College of Horticulture, Northwest A&F University, Yangling, 712100, Shaanxi, China.
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Zhang C, Xu L, Zheng X, Liu S, Che F. Role of Ash1l in Tourette syndrome and other neurodevelopmental disorders. Dev Neurobiol 2021; 81:79-91. [PMID: 33258273 PMCID: PMC8048680 DOI: 10.1002/dneu.22795] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 11/27/2020] [Indexed: 02/06/2023]
Abstract
Ash1l potentially contributes to neurodevelopmental diseases. Although specific Ash1l mutations are rare, they have led to informative studies in animal models that may bring therapeutic advances. Ash1l is highly expressed in the brain and correlates with the neuropathology of Tourette syndrome (TS), autism spectrum disorder, and intellectual disability during development, implicating shared epigenetic factors and overlapping neuropathological mechanisms. Functional convergence of Ash1l generated several significant signaling pathways: chromatin remodeling and transcriptional regulation, protein synthesis and cellular metabolism, and synapse development and function. Here, we systematically review the literature on Ash1l, including its discovery, expression, function, regulation, implication in the nervous system, signaling pathway, mutations, and putative involvement in TS and other neurodevelopmental traits. Such findings highlight Ash1l pleiotropy and the necessity of transcending a single gene to complicated mechanisms of network convergence underlying these diseases. With the progress in functional genomic analysis (highlighted in this review), and although the importance and necessity of Ash1l becomes increasingly apparent in the medical field, further research is required to discover the precise function and molecular regulatory mechanisms related to Ash1l. Thus, a new perspective is proposed for basic scientific research and clinical interventions for cross-disorder diseases.
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Affiliation(s)
- Cheng Zhang
- Department of NeurologyThe Eleventh Clinical Medical College of Qingdao University, Linyi People's HospitalLinyiChina
| | - Lulu Xu
- Department of Geriatric MedicineThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Xueping Zheng
- Department of Geriatric MedicineThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Shiguo Liu
- Medical Genetic DepartmentThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Fengyuan Che
- Department of NeurologyThe Eleventh Clinical Medical College of Qingdao University, Linyi People's HospitalLinyiChina
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36
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The Role of H3K4 Trimethylation in CpG Islands Hypermethylation in Cancer. Biomolecules 2021; 11:biom11020143. [PMID: 33499170 PMCID: PMC7912453 DOI: 10.3390/biom11020143] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/30/2020] [Accepted: 01/15/2021] [Indexed: 01/01/2023] Open
Abstract
CpG methylation in transposons, exons, introns and intergenic regions is important for long-term silencing, silencing of parasitic sequences and alternative promoters, regulating imprinted gene expression and determining X chromosome inactivation. Promoter CpG islands, although rich in CpG dinucleotides, are unmethylated and remain so during all phases of mammalian embryogenesis and development, except in specific cases. The biological mechanisms that contribute to the maintenance of the unmethylated state of CpG islands remain elusive, but the modification of established DNA methylation patterns is a common feature in all types of tumors and is considered as an event that intrinsically, or in association with genetic lesions, feeds carcinogenesis. In this review, we focus on the latest results describing the role that the levels of H3K4 trimethylation may have in determining the aberrant hypermethylation of CpG islands in tumors.
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RUNX3 methylation drives hypoxia-induced cell proliferation and antiapoptosis in early tumorigenesis. Cell Death Differ 2020; 28:1251-1269. [PMID: 33116296 PMCID: PMC8027031 DOI: 10.1038/s41418-020-00647-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 09/21/2020] [Accepted: 10/13/2020] [Indexed: 12/11/2022] Open
Abstract
Inactivation of tumor suppressor Runt-related transcription factor 3 (RUNX3) plays an important role during early tumorigenesis. However, posttranslational modifications (PTM)-based mechanism for the inactivation of RUNX3 under hypoxia is still not fully understood. Here, we demonstrate a mechanism that G9a, lysine-specific methyltransferase (KMT), modulates RUNX3 through PTM under hypoxia. Hypoxia significantly increased G9a protein level and G9a interacted with RUNX3 Runt domain, which led to increased methylation of RUNX3 at K129 and K171. This methylation inactivated transactivation activity of RUNX3 by reducing interactions with CBFβ and p300 cofactors, as well as reducing acetylation of RUNX3 by p300, which is involved in nucleocytoplasmic transport by importin-α1. G9a-mediated methylation of RUNX3 under hypoxia promotes cancer cell proliferation by increasing cell cycle or cell division, while suppresses immune response and apoptosis, thereby promoting tumor growth during early tumorigenesis. Our results demonstrate the molecular mechanism of RUNX3 inactivation by G9a-mediated methylation for cell proliferation and antiapoptosis under hypoxia, which can be a therapeutic or preventive target to control tumor growth during early tumorigenesis.
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38
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Chetverina DA, Lomaev DV, Erokhin MM. Polycomb and Trithorax Group Proteins: The Long Road from Mutations in Drosophila to Use in Medicine. Acta Naturae 2020; 12:66-85. [PMID: 33456979 PMCID: PMC7800605 DOI: 10.32607/actanaturae.11090] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 09/30/2020] [Indexed: 12/12/2022] Open
Abstract
Polycomb group (PcG) and Trithorax group (TrxG) proteins are evolutionarily conserved factors responsible for the repression and activation of the transcription of multiple genes in Drosophila and mammals. Disruption of the PcG/TrxG expression is associated with many pathological conditions, including cancer, which makes them suitable targets for diagnosis and therapy in medicine. In this review, we focus on the major PcG and TrxG complexes, the mechanisms of PcG/TrxG action, and their recruitment to chromatin. We discuss the alterations associated with the dysfunction of a number of factors of these groups in oncology and the current strategies used to develop drugs based on small-molecule inhibitors.
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Affiliation(s)
- D. A. Chetverina
- Institute of Gene Biology, Russian Academy of Sciences, Moscow, 119334 Russia
| | - D. V. Lomaev
- Institute of Gene Biology, Russian Academy of Sciences, Moscow, 119334 Russia
| | - M. M. Erokhin
- Institute of Gene Biology, Russian Academy of Sciences, Moscow, 119334 Russia
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39
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Xu B, Qin T, Yu J, Giordano TJ, Sartor MA, Koenig RJ. Novel role of ASH1L histone methyltransferase in anaplastic thyroid carcinoma. J Biol Chem 2020; 295:8834-8845. [PMID: 32398261 DOI: 10.1074/jbc.ra120.013530] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 05/05/2020] [Indexed: 12/14/2022] Open
Abstract
Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies, with an average life expectancy of ∼6 months from the time of diagnosis. The genetic and epigenetic changes that underlie this malignancy are incompletely understood. We found that ASH1-like histone lysine methyltransferase (ASH1L) is overexpressed in ATC relative to the much less aggressive and more common differentiated thyroid cancer. This increased expression was due at least in part to reduced levels of microRNA-200b-3p (miR-200b-3p), which represses ASH1L expression, in ATC. Genetic knockout of ASH1L protein expression in ATC cell lines decreased cell growth both in culture and in mouse xenografts. RNA-Seq analysis of ASH1L knockout versus WT ATC cell lines revealed that ASH1L is involved in the regulation of numerous cancer-related genes and gene sets. The pro-oncogenic long noncoding RNA colon cancer-associated transcript 1 (CCAT1) was one of the most highly (approximately 68-fold) down-regulated transcripts in ASH1L knockout cells. Therefore, we investigated CCAT1 as a potential mediator of the growth-inducing activity of ASH1L. Supporting this hypothesis, CCAT1 knockdown in ATC cells decreased their growth rate, and ChIP-Seq data indicated that CCAT1 is likely a direct target of ASH1L's histone methyltransferase activity. These results indicate that ASH1L contributes to the aggressiveness of ATC and suggest that ASH1L, along with its upstream regulator miR-200b-3p and its downstream mediator CCAT1, represents a potential therapeutic target in ATC.
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Affiliation(s)
- Bin Xu
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
| | - Tingting Qin
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Jingcheng Yu
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Thomas J Giordano
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Maureen A Sartor
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Ronald J Koenig
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
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40
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Gsell C, Richly H, Coin F, Naegeli H. A chromatin scaffold for DNA damage recognition: how histone methyltransferases prime nucleosomes for repair of ultraviolet light-induced lesions. Nucleic Acids Res 2020; 48:1652-1668. [PMID: 31930303 PMCID: PMC7038933 DOI: 10.1093/nar/gkz1229] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 12/18/2019] [Accepted: 12/23/2019] [Indexed: 02/07/2023] Open
Abstract
The excision of mutagenic DNA adducts by the nucleotide excision repair (NER) pathway is essential for genome stability, which is key to avoiding genetic diseases, premature aging, cancer and neurologic disorders. Due to the need to process an extraordinarily high damage density embedded in the nucleosome landscape of chromatin, NER activity provides a unique functional caliper to understand how histone modifiers modulate DNA damage responses. At least three distinct lysine methyltransferases (KMTs) targeting histones have been shown to facilitate the detection of ultraviolet (UV) light-induced DNA lesions in the difficult to access DNA wrapped around histones in nucleosomes. By methylating core histones, these KMTs generate docking sites for DNA damage recognition factors before the chromatin structure is ultimately relaxed and the offending lesions are effectively excised. In view of their function in priming nucleosomes for DNA repair, mutations of genes coding for these KMTs are expected to cause the accumulation of DNA damage promoting cancer and other chronic diseases. Research on the question of how KMTs modulate DNA repair might pave the way to the development of pharmacologic agents for novel therapeutic strategies.
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Affiliation(s)
- Corina Gsell
- Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Winterthurerstrasse 260, 8057 Zurich, Switzerland
| | - Holger Richly
- Boehringer Ingelheim Pharma, Department of Molecular Biology, Birkendorfer Str. 65, 88397 Biberach an der Riß, Germany
| | - Frédéric Coin
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Equipe Labélisée Ligue contre le Cancer, Illkirch Cedex, Strasbourg, France
| | - Hanspeter Naegeli
- Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Winterthurerstrasse 260, 8057 Zurich, Switzerland
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Abstract
Trithorax histone methyltransferase Ash1/ASH1L is tightly regulated because it activates developmental gene transcription and counteracts Polycomb silencing. In this issue of Structure, Lee et al. (2019) and Hou et al. (2019) report the crystal structure of ASH1L bound to its activator MRG15 and suggest a mechanism that releases ASH1L auto-inhibition.
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42
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Genetic Dissection Reveals the Role of Ash1 Domains in Counteracting Polycomb Repression. G3-GENES GENOMES GENETICS 2019; 9:3801-3812. [PMID: 31540973 PMCID: PMC6829142 DOI: 10.1534/g3.119.400579] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Antagonistic functions of Polycomb and Trithorax proteins are essential for proper development of all metazoans. While the Polycomb proteins maintain the repressed state of many key developmental genes, the Trithorax proteins ensure that these genes stay active in cells where they have to be expressed. Ash1 is the Trithorax protein that was proposed to counteract Polycomb repression by methylating lysine 36 of histone H3. However, it was recently shown that genetic replacement of Drosophila histone H3 with the variant that carried Arginine instead of Lysine at position 36 did not impair the ability of Ash1 to counteract Polycomb repression. This argues that Ash1 counteracts Polycomb repression by methylating yet unknown substrate(s) and that it is time to look beyond Ash1 methyltransferase SET domain, at other evolutionary conserved parts of the protein that received little attention. Here we used Drosophila genetics to demonstrate that Ash1 requires each of the BAH, PHD and SET domains to counteract Polycomb repression, while AT hooks are dispensable. Our findings argue that, in vivo, Ash1 acts as a multimer. Thereby it can combine the input of the SET domain and PHD-BAH cassette residing in different peptides. Finally, using new loss of function alleles, we show that zygotic Ash1 is required to prevent erroneous repression of homeotic genes of the bithorax complex in the embryo.
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43
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Li J, Ahn JH, Wang GG. Understanding histone H3 lysine 36 methylation and its deregulation in disease. Cell Mol Life Sci 2019; 76:2899-2916. [PMID: 31147750 PMCID: PMC11105573 DOI: 10.1007/s00018-019-03144-y] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 05/10/2019] [Indexed: 12/13/2022]
Abstract
Methylation of histone H3 lysine 36 (H3K36) plays crucial roles in the partitioning of chromatin to distinctive domains and the regulation of a wide range of biological processes. Trimethylation of H3K36 (H3K36me3) demarcates body regions of the actively transcribed genes, providing signals for modulating transcription fidelity, mRNA splicing and DNA damage repair; and di-methylation of H3K36 (H3K36me2) spreads out within large intragenic regions, regulating distribution of histone H3 lysine 27 trimethylation (H3K27me3) and possibly DNA methylation. These H3K36 methylation-mediated events are biologically crucial and controlled by different classes of proteins responsible for either 'writing', 'reading' or 'erasing' of H3K36 methylation marks. Deregulation of H3K36 methylation and related regulatory factors leads to pathogenesis of disease such as developmental syndrome and cancer. Additionally, recurrent mutations of H3K36 and surrounding histone residues are detected in human tumors, further highlighting the importance of H3K36 in biology and medicine. This review will elaborate on current advances in understanding H3K36 methylation and related molecular players during various chromatin-templated cellular processes, their crosstalks with other chromatin factors, as well as their deregulations in the diseased contexts.
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Affiliation(s)
- Jie Li
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, 27599, USA
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Jeong Hyun Ahn
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, 27599, USA
- Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Gang Greg Wang
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, 27599, USA.
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
- Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
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44
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Sneppen K, Ringrose L. Theoretical analysis of Polycomb-Trithorax systems predicts that poised chromatin is bistable and not bivalent. Nat Commun 2019; 10:2133. [PMID: 31086177 PMCID: PMC6513952 DOI: 10.1038/s41467-019-10130-2] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 04/12/2019] [Indexed: 12/15/2022] Open
Abstract
Polycomb (PcG) and Trithorax (TrxG) group proteins give stable epigenetic memory of silent and active gene expression states, but also allow poised states in pluripotent cells. Here we systematically address the relationship between poised, active and silent chromatin, by integrating 73 publications on PcG/TrxG biochemistry into a mathematical model comprising 144 nucleosome modification states and 8 enzymatic reactions. Our model predicts that poised chromatin is bistable and not bivalent. Bivalent chromatin, containing opposing active and silent modifications, is present as an unstable background population in all system states, and different subtypes co-occur with active and silent chromatin. In contrast, bistability, in which the system switches frequently between stable active and silent states, occurs under a wide range of conditions at the transition between monostable active and silent system states. By proposing that bistability and not bivalency is associated with poised chromatin, this work has implications for understanding the molecular nature of pluripotency. Polycomb and Trithorax group proteins regulate silent and active gene expression states, but also allow poised states in pluripotent cells. Here the authors present a mathematical model that integrates data on Polycomb/ Trithorax biochemistry into a single coherent framework which predicts that poised chromatin is not bivalent as previously proposed, but is bistable, meaning that the system switches frequently between stable active and silent states.
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Affiliation(s)
- Kim Sneppen
- Center for Models of Life, Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, 2100, Copenhagen, Denmark.
| | - Leonie Ringrose
- Integrated Research Institute for Life Sciences, Humboldt-Universität zu Berlin, Philippstrasse 13, Haus 22, 10115, Berlin, Germany.
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45
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Dorafshan E, Kahn TG, Glotov A, Savitsky M, Walther M, Reuter G, Schwartz YB. Ash1 counteracts Polycomb repression independent of histone H3 lysine 36 methylation. EMBO Rep 2019; 20:embr.201846762. [PMID: 30833342 DOI: 10.15252/embr.201846762] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 01/31/2019] [Accepted: 02/05/2019] [Indexed: 12/11/2022] Open
Abstract
Polycomb repression is critical for metazoan development. Equally important but less studied is the Trithorax system, which safeguards Polycomb target genes from the repression in cells where they have to remain active. It was proposed that the Trithorax system acts via methylation of histone H3 at lysine 4 and lysine 36 (H3K36), thereby inhibiting histone methyltransferase activity of the Polycomb complexes. Here we test this hypothesis by asking whether the Trithorax group protein Ash1 requires H3K36 methylation to counteract Polycomb repression. We show that Ash1 is the only Drosophila H3K36-specific methyltransferase necessary to prevent excessive Polycomb repression of homeotic genes. Unexpectedly, our experiments reveal no correlation between the extent of H3K36 methylation and the resistance to Polycomb repression. Furthermore, we find that complete substitution of the zygotic histone H3 with a variant in which lysine 36 is replaced by arginine does not cause excessive repression of homeotic genes. Our results suggest that the model, where the Trithorax group proteins methylate histone H3 to inhibit the histone methyltransferase activity of the Polycomb complexes, needs revision.
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Affiliation(s)
| | - Tatyana G Kahn
- Department of Molecular Biology, Umeå University, Umeå, Sweden
| | | | | | - Matthias Walther
- Institute of Developmental Genetics, Martin-Luther University of Halle-Wittenberg, Halle, Germany.,Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Gunter Reuter
- Institute of Developmental Genetics, Martin-Luther University of Halle-Wittenberg, Halle, Germany
| | - Yuri B Schwartz
- Department of Molecular Biology, Umeå University, Umeå, Sweden
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46
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Hou P, Huang C, Liu CP, Yang N, Yu T, Yin Y, Zhu B, Xu RM. Structural Insights into Stimulation of Ash1L's H3K36 Methyltransferase Activity through Mrg15 Binding. Structure 2019; 27:837-845.e3. [PMID: 30827843 DOI: 10.1016/j.str.2019.01.015] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 01/01/2019] [Accepted: 01/28/2019] [Indexed: 12/18/2022]
Abstract
The evolutionarily conserved Trithorax group protein Ash1 is a SET domain histone methyltransferase that mono- and dimethylates lysine 36 of histone H3 (H3K36). Ash1 forms a complex with Mrg15 and Nurf55, and the binding of Mrg15 greatly stimulates the catalytic activity of Ash1, yet the underlying molecular mechanisms remain unknown. Here we report the crystal structure of the tandem Mrg15-interacting and SET domains of human Ash1L in complex with Mrg15. Ash1L interacts with Mrg15 principally via a segment located N-terminal to the catalytic SET domain. Surprisingly, an autoinhibitory loop in the post-SET region of Ash1L is destabilized on Mrg15 binding despite no direct contact. Dynamics of the autoinhibitory loop can be attributed to subtle structural changes of the S-adenosylmethionine (SAM) binding pocket induced by Mrg15 binding, implicating a mechanism of conformational coupling between SAM and substrate binding sites. The findings broaden the understanding of regulation of H3K36 methyltransferases.
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Affiliation(s)
- Peini Hou
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 10049, China
| | - Chang Huang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Chao-Pei Liu
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Na Yang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, China
| | - Tianshu Yu
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Yuxin Yin
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Bing Zhu
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 10049, China.
| | - Rui-Ming Xu
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 10049, China.
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47
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Lee Y, Yoon E, Cho S, Schmähling S, Müller J, Song JJ. Structural Basis of MRG15-Mediated Activation of the ASH1L Histone Methyltransferase by Releasing an Autoinhibitory Loop. Structure 2019; 27:846-852.e3. [PMID: 30827841 DOI: 10.1016/j.str.2019.01.016] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 12/23/2018] [Accepted: 01/28/2019] [Indexed: 12/20/2022]
Abstract
Human ASH1L is the catalytic subunit of the conserved histone methyltransferase (HMTase) complex AMC that dimethylates lysine 36 in histone H3 (H3K36me2) to promote gene transcription in mammals and flies. Unlike AMC, ASH1L alone shows poor catalytic activity, because access to its substrate binding pocket is blocked by an autoinhibitory loop (AI loop) from the postSET domain. We report the crystal structure of the minimal catalytic active AMC complex containing ASH1L and its partner subunit MRG15. The structure reveals how binding of the MRG domain of MRG15 to a conserved FxLP motif in ASH1L results in the displacement of the AI loop to permit substrates to access the catalytic pocket of the ASH1L SET domain. Together, ASH1L activation by MRG15 therefore represents a delicate regulatory mechanism for how a cofactor activates an SET domain HMTase by releasing autoinhibition.
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Affiliation(s)
- Yoonjung Lee
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Korea; Center for Bioanalysis, Korea Research Institute of Standards and Science, 267 Gajeong-ro, Yuseong-gu, Daejeon 34113, Korea
| | - Eojin Yoon
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Korea
| | - Saehyun Cho
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Korea
| | - Sigrun Schmähling
- MPI of Biochemistry, Laboratory of Chromatin Biology, Am Klopferspitz 18, 82152 Martinsried, Germany
| | - Jürg Müller
- MPI of Biochemistry, Laboratory of Chromatin Biology, Am Klopferspitz 18, 82152 Martinsried, Germany
| | - Ji-Joon Song
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Korea.
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48
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Cinel SD, Taylor SJ. Prolonged Bat Call Exposure Induces a Broad Transcriptional Response in the Male Fall Armyworm ( Spodoptera frugiperda; Lepidoptera: Noctuidae) Brain. Front Behav Neurosci 2019; 13:36. [PMID: 30863292 PMCID: PMC6399161 DOI: 10.3389/fnbeh.2019.00036] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Accepted: 02/11/2019] [Indexed: 12/22/2022] Open
Abstract
Predation risk induces broad behavioral and physiological responses that have traditionally been considered acute and transitory. However, prolonged or frequent exposure to predators and the sensory cues of their presence they broadcast to the environment impact long-term prey physiology and demographics. Though several studies have assessed acute and chronic stress responses in varied taxa, these attempts have often involved a priori expectations of the molecular pathways involved in physiological responses, such as glucocorticoid pathways and neurohormone production in vertebrates. While relatively little is known about physiological and molecular predator-induced stress in insects, many dramatic insect defensive behaviors have evolved to combat selection by predators. For instance, several moth families, such as Noctuidae, include members equipped with tympanic organs that allow the perception of ultrasonic bat calls and facilitate predation avoidance by eliciting evasive aerial flight maneuvers. In this study, we exposed adult male fall armyworm (Spodoptera frugiperda) moths to recorded ultrasonic bat foraging and attack calls for a prolonged period and constructed a de novo transcriptome based on brain tissue from predator cue-exposed relative to control moths kept in silence. Differential expression analysis revealed that 290 transcripts were highly up- or down-regulated among treatment tissues, with many annotating to noteworthy proteins, including a heat shock protein and an antioxidant enzyme involved in cellular stress. Though nearly 50% of differentially expressed transcripts were unannotated, those that were are implied in a broad range of cellular functions within the insect brain, including neurotransmitter metabolism, ionotropic receptor expression, mitochondrial metabolism, heat shock protein activity, antioxidant enzyme activity, actin cytoskeleton dynamics, chromatin binding, methylation, axonal guidance, cilia development, and several signaling pathways. The five most significantly overrepresented Gene Ontology terms included chromatin binding, macromolecular complex binding, glutamate synthase activity, glutamate metabolic process, and glutamate biosynthetic process. As a first assessment of transcriptional responses to ecologically relevant auditory predator cues in the brain of moth prey, this study lays the foundation for examining the influence of these differentially expressed transcripts on insect behavior, physiology, and life history within the framework of predation risk, as observed in ultrasound-sensitive Lepidoptera and other 'eared' insects.
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Affiliation(s)
- Scott D Cinel
- Illinois Natural History Survey, Prairie Research Institute, University of Illinois at Urbana-Champaign, Champaign, IL, United States.,Insect Evolution, Behavior, and Genomics Lab, Florida Museum of Natural History, University of Florida, Gainesville, FL, United States
| | - Steven J Taylor
- Illinois Natural History Survey, Prairie Research Institute, University of Illinois at Urbana-Champaign, Champaign, IL, United States.,Colorado College, Colorado Springs, CO, United States
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49
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Wilkinson AW, Diep J, Dai S, Liu S, Ooi YS, Song D, Li TM, Horton JR, Zhang X, Liu C, Trivedi DV, Ruppel KM, Vilches-Moure JG, Casey KM, Mak J, Cowan T, Elias JE, Nagamine CM, Spudich JA, Cheng X, Carette JE, Gozani O. SETD3 is an actin histidine methyltransferase that prevents primary dystocia. Nature 2018; 565:372-376. [PMID: 30626964 PMCID: PMC6511263 DOI: 10.1038/s41586-018-0821-8] [Citation(s) in RCA: 106] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Accepted: 11/30/2018] [Indexed: 01/17/2023]
Abstract
For over fifty years, the methylation of mammalian actin at histidine 73
(actin-H73me) has been known to exist1. Beyond mammals, we find that actin-H73me is conserved
in several additional model animal and plant organisms. Despite the
pervasiveness of H73me, its function is enigmatic, and the enzyme generating
this modification is unknown. Here, we identify SETD3 (SET
domain protein 3) as the physiologic
actin histidine 73 methyltransferase. Structural studies reveal that an
extensive network of interactions clamps the actin peptide on the SETD3 surface
to properly orient H73 within the catalytic pocket and facilitate methyl
transfer. H73me reduces the nucleotide exchange rate on actin monomers and
modestly accelerates actin filament assembly. Mice lacking SETD3 show complete
loss of actin-H73me in multiple tissues and quantitative proteomics singles out
actin-H73 as the principal physiologic SETD3 substrate. SETD3 deficient female
mice have severely decreased litter sizes due to primary maternal dystocia that
is refractory to ecbolic induction agents. Further, depletion of SETD3 impairs
signal-induced contraction in primary human uterine smooth muscle cells.
Together, our results identify the first mammalian protein histidine
methyltransferase and uncover a pivotal role for SETD3 and actin-H73me in the
regulation of smooth muscle contractility. Our data also support the broader
hypothesis where protein histidine methylation acts as a common regulatory
mechanism.
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Affiliation(s)
| | - Jonathan Diep
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
| | - Shaobo Dai
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shuo Liu
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Yaw Shin Ooi
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
| | - Dan Song
- Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA
| | - Tie-Mei Li
- Department of Biology, Stanford University, Stanford, CA, USA
| | - John R Horton
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xing Zhang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Chao Liu
- Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA
| | - Darshan V Trivedi
- Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA
| | - Katherine M Ruppel
- Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA
| | - José G Vilches-Moure
- Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Kerriann M Casey
- Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | | | - Tina Cowan
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Joshua E Elias
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA
| | - Claude M Nagamine
- Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - James A Spudich
- Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA
| | - Xiaodong Cheng
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Jan E Carette
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
| | - Or Gozani
- Department of Biology, Stanford University, Stanford, CA, USA.
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50
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Bicocca VT, Ormsby T, Adhvaryu KK, Honda S, Selker EU. ASH1-catalyzed H3K36 methylation drives gene repression and marks H3K27me2/3-competent chromatin. eLife 2018; 7:41497. [PMID: 30468429 PMCID: PMC6251624 DOI: 10.7554/elife.41497] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 10/31/2018] [Indexed: 12/31/2022] Open
Abstract
Methylation of histone H3 at lysine 36 (H3K36me), a widely-distributed chromatin mark, largely results from association of the lysine methyltransferase (KMT) SET-2 with RNA polymerase II (RNAPII), but most eukaryotes also have additional H3K36me KMTs that act independently of RNAPII. These include the orthologs of ASH1, which are conserved in animals, plants, and fungi but whose function and control are poorly understood. We found that Neurospora crassa has just two H3K36 KMTs, ASH1 and SET-2, and were able to explore the function and distribution of each enzyme independently. While H3K36me deposited by SET-2 marks active genes, inactive genes are modified by ASH1 and its activity is critical for their repression. ASH1-marked chromatin can be further modified by methylation of H3K27, and ASH1 catalytic activity modulates the accumulation of H3K27me2/3 both positively and negatively. These findings provide new insight into ASH1 function, H3K27me2/3 establishment, and repression in facultative heterochromatin. Not all genes in a cell’s DNA are active all the time. There are several ways to control this activity. One is by altering how the DNA is packaged into cells. DNA strands are wrapped around proteins called histones to form nucleosomes. Nucleosomes can then be packed together tightly, to restrict access to the DNA at genes that are not active, or loosely to allow access to the DNA of active genes. Chemical marks, such as methyl groups, can be attached to particular sites on histones to influence how they pack together. One important site for such marks is known as position 36 on histone H3, or H3K36 for short. Correctly adding methyl groups to this site is critical for normal development, and when this process goes wrong it can lead to diseases like cancer. An enzyme called SET-2 oversees the methylation of H3K36 in fungi, plants and animals. However, many species have several other enzymes that can also add methyl groups to H3K36, and their roles are less clear. A type of fungus called Neurospora crassa contains just two enzymes that can add methyl groups to H3K36: SET-2, and another enzyme called ASH1. By performing experiments that inactivated SET-2 and ASH1 in this fungus, Bicocca et al. found that each enzyme works on a different set of genes. Genes in regions marked by SET-2 were accessible for the cell to use, while genes marked by ASH1 were inaccessible. ASH1 also affects whether a methyl group is added to another site on histone H3. This mark is important for controlling the activity of genes that are critical for development. ASH1 is found in many other organisms, including humans. The results presented by Bicocca et al. could therefore be built upon to understand the more complicated systems for regulating H3K36 methylation in other species. From there, we can investigate how to intervene when things go wrong during developmental disorders and cancer.
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Affiliation(s)
- Vincent T Bicocca
- Institute of Molecular Biology, University of Oregon, Eugene, United States
| | - Tereza Ormsby
- Department of Biochemistry Faculty of Science, Charles University, Prague, Czech Republic
| | | | - Shinji Honda
- Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Eric U Selker
- Institute of Molecular Biology, University of Oregon, Eugene, United States
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