2. Academic Validation
  3. Uncoupling histone modification crosstalk by engineering lysine demethylase LSD1

Uncoupling histone modification crosstalk by engineering lysine demethylase LSD1

  • Nat Chem Biol. 2024 Jul 4. doi: 10.1038/s41589-024-01671-9.
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 Caroli 3,  Katherine Neal 1 2,  Brian Ibeabuchi 1 2,  Zuzer Dhoondia 1 6,  Mitzi I Kuroda 1 6,  Brian B Liau 4 5,  Samuel Beck 7,  Andrea Mattevi 8,  Philip A Cole 9 10
Affiliations

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 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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