Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation
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.
Authors
- Brian D. Strahl (ORCID: https://orcid.org/0000-0002-4947-6259)
- Shuai Yang (ORCID: https://orcid.org/0000-0001-9637-7758)
- Scott B. Rothbart (ORCID: https://orcid.org/0000-0003-1631-5392)
- Tatiana G. Kutateladze (ORCID: https://orcid.org/0000-0001-7375-6990)
- Patricia Ernst (ORCID: https://orcid.org/0000-0001-7638-2939)
- Soumi Biswas (ORCID: https://orcid.org/0000-0002-6944-1475)
- Suk Min Jang
- Brianna J. Klein (ORCID: https://orcid.org/0000-0003-2479-8013)
- Jacques Côté (ORCID: https://orcid.org/0000-0001-6751-555X)
- Michael L. Cleary (ORCID: https://orcid.org/0000-0001-7127-3223)
- Lei Zeng (ORCID: https://orcid.org/0000-0002-4236-6735)
- Ming‐Ming Zhou (ORCID: https://orcid.org/0000-0002-7049-0573)
- Kendra R. Vann (ORCID: https://orcid.org/0000-0002-6366-6112)
- Rajal Sharma
- Xiaobing Shi (ORCID: https://orcid.org/0000-0001-5242-8189)
- Ka Lung Cheung
- Maëva Devoucoux (ORCID: https://orcid.org/0000-0002-0965-2852)
- Kevin Lin (ORCID: https://orcid.org/0000-0002-1236-9847)
- Martin J. Walsh (ORCID: https://orcid.org/0000-0001-8339-8285)
- Chih-Chao Hsu (ORCID: https://orcid.org/0000-0001-9552-1949)
- Ruben D Rosas Ospina (ORCID: https://orcid.org/0000-0002-7344-4548)
- Jovylyn Gatchalian (ORCID: https://orcid.org/0000-0003-0322-4619)
- Adam H. Tencer
- Hongwen Xuan (ORCID: https://orcid.org/0000-0002-4095-6352)
- Yue Lu (ORCID: https://orcid.org/0000-0002-5479-9095)
- Qin Li (ORCID: https://orcid.org/0000-0002-7651-5057)
- Jianlong Wang (ORCID: https://orcid.org/0000-0002-1317-6457)
- Qiong Tong (ORCID: https://orcid.org/0009-0001-9348-9065)
- Li Zhu
- Catherine Lachance
- Lorena Alamillo (ORCID: https://orcid.org/0000-0002-2622-0277)
Institutions
- University of North Carolina at Chapel Hill (US)
- Van Andel Institute (US)
- The University of Texas MD Anderson Cancer Center (US)
- Columbia University Irving Medical Center (US)
- Université Laval (CA)
- University of Colorado Anschutz Medical Campus (US)
- University of Pennsylvania (US)
- University of Colorado Denver (US)
- Stanford University (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-06
- DOI
- https://doi.org/10.1038/s41467-025-57556-5
- Citations
- 3
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- National Institute on Aging
- National Heart, Lung, and Blood Institute
- National Cancer Institute