APA
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Vann, K. R., Sharma, R., Hsu, C.-C., Devoucoux, M., Tencer, A., Zeng, L., … Kutateladze, T. (2025). Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation. Nature Communications.
Chicago/Turabian
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Vann, K. R., Rajal Sharma, Chih-Chao Hsu, Maëva Devoucoux, A. Tencer, Lei Zeng, Kevin Lin, et al. “Structure-Function Relationship of ASH1L and Histone H3K36 and H3K4 Methylation.” Nature Communications (2025).
MLA
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Vann, K. R., et al. “Structure-Function Relationship of ASH1L and Histone H3K36 and H3K4 Methylation.” Nature Communications, 2025.
BibTeX Click to copy
@article{k2025a,
title = {Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation},
year = {2025},
journal = {Nature Communications},
author = {Vann, K. R. and Sharma, Rajal and Hsu, Chih-Chao and Devoucoux, Maëva and Tencer, A. and Zeng, Lei and Lin, Kevin and Zhu, Li and Li, Qin and Lachance, C. and Ospina, Ruben Rosas and Tong, Qiong and Cheung, Ka Lung and Yang, Shuai and Biswas, Soumi and Xuan, Hongwen and Gatchalian, J. and Alamillo, Lorena and Wang, Jianlong and Jang, S. and Klein, B. J. and Lu, Yue and Ernst, Patricia and Strahl, B. and Rothbart, Scott B. and Walsh, M. and Cleary, Michael L. and Côté, Jacques and Shi, Xiaobing and Zhou, Ming-Ming and Kutateladze, T.}
}
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. Mutations of the histone H3K36-specific methyltransferase ASH1L have been linked to several human diseases. Here, the authors report the mechanism by which three C-terminal domains in ASH1L regulate its enzymatic activity and interact with chromatin.