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<p>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 (ASH1L<sub>BD</sub>), a plant homeodomain (ASH1L<sub>PHD</sub>) finger, and a bromo-adjacent homology (ASH1L<sub>BAH</sub>) domain, structurally characterize these domains, describe their mechanisms of action, and explore functional crosstalk between them. We find that ASH1L<sub>PHD</sub> recognizes H3K4me2/3, whereas the neighboring ASH1L<sub>BD</sub> and ASH1L<sub>BAH</sub> have DNA binding activities. The DNA binding function of ASH1L<sub>BAH</sub> is a driving force for the association of ASH1L with the linker DNA in the nucleosome, and the large interface with ASH1L<sub>PHD</sub> stabilizes the ASH1L<sub>BAH</sub> 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 ASH1L<sub>PHD</sub> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月6日

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  • 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

摘要

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.