Uncoupling histone modification crosstalk by engineering lysine demethylase LSD1
- PMID: 38965385
- PMCID: PMC11699879
- DOI: 10.1038/s41589-024-01671-9
Uncoupling histone modification crosstalk by engineering lysine demethylase LSD1
Abstract
Biochemical crosstalk between two or more histone modifications is often observed in epigenetic enzyme regulation, but its functional significance in cells has been difficult to discern. Previous enzymatic studies revealed that Lys14 acetylation of histone H3 can inhibit Lys4 demethylation by lysine-specific demethylase 1 (LSD1). In the present study, we engineered a mutant form of LSD1, Y391K, which renders the nucleosome demethylase activity of LSD1 insensitive to Lys14 acetylation. K562 cells with the Y391K LSD1 CRISPR knockin show decreased expression of a set of genes associated with cellular adhesion and myeloid leukocyte activation. Chromatin profiling revealed that the cis-regulatory regions of these silenced genes display a higher level of H3 Lys14 acetylation, and edited K562 cells show diminished H3 mono-methyl Lys4 near these silenced genes, consistent with a role for enhanced LSD1 demethylase activity. These findings illuminate the functional consequences of disconnecting histone modification crosstalk for a key epigenetic enzyme.
© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.
Conflict of interest statement
Competing interests: P.A.C. is a co-founder of Acylin Therapeutics, which is involved in developing epigenetic agents, and has been a consultant for the pharmaceutical companies AbbVie and Constellation. He also is a co-inventor on US patent 11,565,994 B2 that concerns LSD1 and CoREST complex inhibitors. B.B.L. has received research funding from Eisai and AstraZeneca and is a shareholder and member of the scientific advisory board of Light Horse Therapeutics. The other authors declare no competing interests.
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- R01 AG068179/AG/NIA NIH HHS/United States
- R37 GM062437/GM/NIGMS NIH HHS/United States
- R35 GM126944/GM/NIGMS NIH HHS/United States
- GM149229/U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
- N/A/Charles A. King Trust
- R56 AG082796/AG/NIA NIH HHS/United States
- SCOR/Leukemia and Lymphoma Society (Leukemia & Lymphoma Society)
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- 826614/American Heart Association (American Heart Association, Inc.)
- PF20-105-01-DMC/American Cancer Society (American Cancer Society, Inc.)
- GM126944/U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
- DP2 GM137494/GM/NIGMS NIH HHS/United States
- R35 GM149229/GM/NIGMS NIH HHS/United States
- R01 GM062437/GM/NIGMS NIH HHS/United States
- AG068179/U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
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