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  3. Chromatin profiling in human neurons reveals aberrant roles for histone acetylation and BET family proteins in schizophrenia

Chromatin profiling in human neurons reveals aberrant roles for histone acetylation and BET family proteins in schizophrenia

  • Nat Commun. 2022 Apr 22;13(1):2195. doi: 10.1038/s41467-022-29922-0.
Lorna A Farrelly  # 1,  Shuangping Zheng  # 2,  Nadine Schrode 3,  Aaron Topol 4,  Natarajan V Bhanu 5,  Ryan M Bastle 1,  Aarthi Ramakrishnan 1,  Jennifer C Chan 1,  Bulent Cetin 1,  Erin Flaherty 1 3,  Li Shen 1,  Kelly Gleason 6,  Carol A Tamminga 6,  Benjamin A Garcia 5,  Haitao Li 7,  Kristen J Brennand 8 9 10 11 12,  Ian Maze 13 14 15
Affiliations

Affiliations

  • 1 Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • 2 Beijing Advanced Innovation Center for Structural Biology, MOE Key Laboratory of Protein Sciences, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, 100084, Beijing, China.
  • 3 Department of Genetics and Genomic Sciences, Pamela Sklar Division of Psychiatric Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • 4 Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • 5 Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 6 Department of Psychiatry, University of Texas Southwestern Medical School, Dallas, TX, 75390, USA.
  • 7 Beijing Advanced Innovation Center for Structural Biology, MOE Key Laboratory of Protein Sciences, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, 100084, Beijing, China. lht@tsinghua.edu.cn.
  • 8 Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. kristen.brennand@yale.edu.
  • 9 Department of Genetics and Genomic Sciences, Pamela Sklar Division of Psychiatric Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. kristen.brennand@yale.edu.
  • 10 Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. kristen.brennand@yale.edu.
  • 11 Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. kristen.brennand@yale.edu.
  • 12 Departments of Psychiatry and Genetics, Wu Tsai Institute, Yale School of Medicine, New Haven, CT, 065109, USA. kristen.brennand@yale.edu.
  • 13 Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. ian.maze@mssm.edu.
  • 14 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. ian.maze@mssm.edu.
  • 15 Howard Hughes Medical Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. ian.maze@mssm.edu.
  • # Contributed equally.
PMID: 35459277 DOI: 10.1038/s41467-022-29922-0
Abstract

Schizophrenia (SZ) is a psychiatric disorder with complex genetic risk dictated by interactions between hundreds of risk variants. Epigenetic factors, such as histone posttranslational modifications (PTMs), have been shown to play critical roles in many neurodevelopmental processes, and when perturbed may also contribute to the precipitation of disease. Here, we apply an unbiased proteomics approach to evaluate combinatorial histone PTMs in human induced pluripotent stem cell (hiPSC)-derived forebrain neurons from individuals with SZ. We observe hyperacetylation of H2A.Z and H4 in neurons derived from SZ cases, results that were confirmed in postmortem human brain. We demonstrate that the bromodomain and extraterminal (BET) protein, BRD4, is a bona fide 'reader' of H2A.Z acetylation, and further provide evidence that BET family protein inhibition ameliorates transcriptional abnormalities in patient-derived neurons. Thus, treatments aimed at alleviating BET protein interactions with hyperacetylated histones may aid in the prevention or treatment of SZ.

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