Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation
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 homeodom...
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2025-03-01
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| Online Access: | https://doi.org/10.1038/s41467-025-57556-5 |
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| author | Kendra R. Vann Rajal Sharma Chih-Chao Hsu Maeva Devoucoux Adam H. Tencer Lei Zeng Kevin Lin Li Zhu Qin Li Catherine Lachance Ruben Rosas Ospina Qiong Tong Ka Lung Cheung Shuai Yang Soumi Biswas Hongwen Xuan Jovylyn Gatchalian Lorena Alamillo Jianlong Wang Suk Min Jang Brianna J. Klein Yue Lu Patricia Ernst Brian D. Strahl Scott B. Rothbart Martin J. Walsh Michael L. Cleary Jacques Côté Xiaobing Shi Ming-Ming Zhou Tatiana G. Kutateladze |
| author_facet | Kendra R. Vann Rajal Sharma Chih-Chao Hsu Maeva Devoucoux Adam H. Tencer Lei Zeng Kevin Lin Li Zhu Qin Li Catherine Lachance Ruben Rosas Ospina Qiong Tong Ka Lung Cheung Shuai Yang Soumi Biswas Hongwen Xuan Jovylyn Gatchalian Lorena Alamillo Jianlong Wang Suk Min Jang Brianna J. Klein Yue Lu Patricia Ernst Brian D. Strahl Scott B. Rothbart Martin J. Walsh Michael L. Cleary Jacques Côté Xiaobing Shi Ming-Ming Zhou Tatiana G. Kutateladze |
| author_sort | Kendra R. Vann |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-55cdb70a767d49bb886b74b90ca47d60 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-55cdb70a767d49bb886b74b90ca47d602025-08-20T01:57:52ZengNature PortfolioNature Communications2041-17232025-03-0116111510.1038/s41467-025-57556-5Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylationKendra R. Vann0Rajal Sharma1Chih-Chao Hsu2Maeva Devoucoux3Adam H. Tencer4Lei Zeng5Kevin Lin6Li Zhu7Qin Li8Catherine Lachance9Ruben Rosas Ospina10Qiong Tong11Ka Lung Cheung12Shuai Yang13Soumi Biswas14Hongwen Xuan15Jovylyn Gatchalian16Lorena Alamillo17Jianlong Wang18Suk Min Jang19Brianna J. Klein20Yue Lu21Patricia Ernst22Brian D. Strahl23Scott B. Rothbart24Martin J. Walsh25Michael L. Cleary26Jacques Côté27Xiaobing Shi28Ming-Ming Zhou29Tatiana G. Kutateladze30Department of Pharmacology, University of Colorado School of MedicineDepartment of Pharmacological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer CenterSt-Patrick Research Group in Basic Oncology, Oncology Division of CHU de Québec-Université Laval Research, Laval University Cancer Research Center, Quebec CityDepartment of Pharmacology, University of Colorado School of MedicineDepartment of Pharmacological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer CenterDepartment of Pathology, Stanford University School of MedicineDepartment of Genetics, University of PennsylvaniaSt-Patrick Research Group in Basic Oncology, Oncology Division of CHU de Québec-Université Laval Research, Laval University Cancer Research Center, Quebec CityDepartment of Pharmacology, University of Colorado School of MedicineDepartment of Pharmacology, University of Colorado School of MedicineDepartment of Pharmacological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Pharmacological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Pharmacology, University of Colorado School of MedicineDepartment of Epigenetics, Van Andel Research InstituteDepartment of Pharmacology, University of Colorado School of MedicineDepartment of Pharmacology, University of Colorado School of MedicineDepartment of Medicine, Columbia Center for Human Development, Columbia University Irving Medical CenterSt-Patrick Research Group in Basic Oncology, Oncology Division of CHU de Québec-Université Laval Research, Laval University Cancer Research Center, Quebec CityDepartment of Pharmacology, University of Colorado School of MedicineDepartment of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer CenterDepartment of Pharmacology, University of Colorado School of MedicineDepartment of Biochemistry & Biophysics, The University of North Carolina School of MedicineDepartment of Epigenetics, Van Andel Research InstituteDepartment of Pharmacological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Pathology, Stanford University School of MedicineSt-Patrick Research Group in Basic Oncology, Oncology Division of CHU de Québec-Université Laval Research, Laval University Cancer Research Center, Quebec CityDepartment of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer CenterDepartment of Pharmacological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Pharmacology, University of Colorado School of MedicineAbstract 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.https://doi.org/10.1038/s41467-025-57556-5 |
| spellingShingle | Kendra R. Vann Rajal Sharma Chih-Chao Hsu Maeva Devoucoux Adam H. Tencer Lei Zeng Kevin Lin Li Zhu Qin Li Catherine Lachance Ruben Rosas Ospina Qiong Tong Ka Lung Cheung Shuai Yang Soumi Biswas Hongwen Xuan Jovylyn Gatchalian Lorena Alamillo Jianlong Wang Suk Min Jang Brianna J. Klein Yue Lu Patricia Ernst Brian D. Strahl Scott B. Rothbart Martin J. Walsh Michael L. Cleary Jacques Côté Xiaobing Shi Ming-Ming Zhou Tatiana G. Kutateladze Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation Nature Communications |
| title | Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation |
| title_full | Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation |
| title_fullStr | Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation |
| title_full_unstemmed | Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation |
| title_short | Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation |
| title_sort | structure function relationship of ash1l and histone h3k36 and h3k4 methylation |
| url | https://doi.org/10.1038/s41467-025-57556-5 |
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