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

Author

Listed:
  • 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
    The University of North Carolina School of Medicine)

  • 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
    Van Andel Research Institute)

  • Ming-Ming Zhou

    (Icahn School of Medicine at Mount Sinai)

  • Tatiana G. Kutateladze

    (University of Colorado School of Medicine)

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.

Suggested Citation

  • 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 & Shua, 2025. "Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57556-5
    DOI: 10.1038/s41467-025-57556-5
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