Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation

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 () and Tatiana G. Kutateladze ()
Additional contact information
Kendra R. Vann: University of Colorado School of Medicine
Rajal Sharma: Icahn School of Medicine at Mount Sinai
Chih-Chao Hsu: The University of Texas MD Anderson Cancer Center
Maeva Devoucoux: Quebec City
Adam H. Tencer: University of Colorado School of Medicine
Lei Zeng: Icahn School of Medicine at Mount Sinai
Kevin Lin: The University of Texas MD Anderson Cancer Center
Li Zhu: Stanford University School of Medicine
Qin Li: University of Pennsylvania
Catherine Lachance: Quebec City
Ruben Rosas Ospina: University of Colorado School of Medicine
Qiong Tong: University of Colorado School of Medicine
Ka Lung Cheung: Icahn School of Medicine at Mount Sinai
Shuai Yang: Icahn School of Medicine at Mount Sinai
Soumi Biswas: University of Colorado School of Medicine
Hongwen Xuan: Van Andel Research Institute
Jovylyn Gatchalian: University of Colorado School of Medicine
Lorena Alamillo: University of Colorado School of Medicine
Jianlong Wang: Columbia University Irving Medical Center
Suk Min Jang: Quebec City
Brianna J. Klein: University of Colorado School of Medicine
Yue Lu: The University of Texas MD Anderson Cancer Center
Patricia Ernst: University of Colorado School of Medicine
Brian D. Strahl: The University of North Carolina School of Medicine
Scott B. Rothbart: Van Andel Research Institute
Martin J. Walsh: Icahn School of Medicine at Mount Sinai
Michael L. Cleary: Stanford University School of Medicine
Jacques Côté: Quebec City
Xiaobing Shi: The University of Texas MD Anderson Cancer Center
Ming-Ming Zhou: Icahn School of Medicine at Mount Sinai
Tatiana G. Kutateladze: University of Colorado School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57556-5

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