Uncoupling histone modification crosstalk by engineering lysine demethylase LSD1

Kwangwoon Lee^#^{1

2}, Marco Barone^#³, Amanda L Waterbury^{4

5}, Hanjie Jiang^{1

2}, Eunju Nam^{1

2}, Sarah E DuBois-Coyne^{1

2}, Samuel D Whedon^{1

2}, Zhipeng A Wang^{1

2}, Jonatan Caroli³, Katherine Neal^{1

2}, Brian Ibeabuchi^{1

2}, Zuzer Dhoondia^{1

6}, Mitzi I Kuroda^{1

6}, Brian B Liau^{4

5}, Samuel Beck⁷, Andrea Mattevi⁸, Philip A Cole^{9

10}

Affiliations

¹ Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
² Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
³ Department of Biology and Biotechnology Lazzaro Spallanzani, University of Pavia, Pavia, Italy.
⁴ Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
⁵ Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁶ Department of Genetics, Harvard Medical School, Boston, MA, USA.
⁷ Department of Dermatology, Boston University School of Medicine & Boston Medical Center, Boston, MA, USA. sambeck@bu.edu.
⁸ Department of Biology and Biotechnology Lazzaro Spallanzani, University of Pavia, Pavia, Italy. andrea.mattevi@unipv.it.
⁹ Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. pacole@bwh.harvard.edu.
¹⁰ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. pacole@bwh.harvard.edu.

^# Contributed equally.

PMID: 38965385
PMCID: PMC11699879 (available on 2026-02-01)
DOI: 10.1038/s41589-024-01671-9

Uncoupling histone modification crosstalk by engineering lysine demethylase LSD1

Kwangwoon Lee et al. Nat Chem Biol. 2025 Feb.

. 2025 Feb;21(2):227-237.

doi: 10.1038/s41589-024-01671-9. Epub 2024 Jul 4.

Authors

Affiliations

¹ Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
² Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
³ Department of Biology and Biotechnology Lazzaro Spallanzani, University of Pavia, Pavia, Italy.
⁴ Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
⁵ Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁶ Department of Genetics, Harvard Medical School, Boston, MA, USA.
⁷ Department of Dermatology, Boston University School of Medicine & Boston Medical Center, Boston, MA, USA. sambeck@bu.edu.
⁸ Department of Biology and Biotechnology Lazzaro Spallanzani, University of Pavia, Pavia, Italy. andrea.mattevi@unipv.it.
⁹ Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. pacole@bwh.harvard.edu.
¹⁰ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. pacole@bwh.harvard.edu.

^# Contributed equally.

PMID: 38965385
PMCID: PMC11699879 (available on 2026-02-01)
DOI: 10.1038/s41589-024-01671-9

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.

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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.

References

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1. Valencia-Sánchez MI et al. Structural Basis of Dot1L Stimulation by Histone H2B Lysine 120 Ubiquitination. Molecular Cell 74, 1010–1019.e6 (2019). - PMC - PubMed
1. Worden EJ, Hoffmann NA, Hicks CW & Wolberger C Mechanism of Cross-talk between H2B Ubiquitination and H3 Methylation by Dot1L. Cell 176, 1490–1501.e12 (2019). - PMC - PubMed

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Uncoupling histone modification crosstalk by engineering lysine demethylase LSD1

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Uncoupling histone modification crosstalk by engineering lysine demethylase LSD1

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