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

Lorna A. Farrelly, Shuangping Zheng, Nadine Schrode, Aaron Topol, Natarajan V. Bhanu, Ryan M. Bastle, Aarthi Ramakrishnan, Jennifer C Chan, Bulent Cetin, Erin Flaherty, Li Shen, Kelly Gleason, Carol A. Tamminga, Benjamin A. Garcia, Haitao Li (), Kristen J. Brennand () and Ian Maze ()
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Lorna A. Farrelly: Icahn School of Medicine at Mount Sinai
Shuangping Zheng: Tsinghua University
Nadine Schrode: Icahn School of Medicine at Mount Sinai
Aaron Topol: Icahn School of Medicine at Mount Sinai
Natarajan V. Bhanu: University of Pennsylvania
Ryan M. Bastle: Icahn School of Medicine at Mount Sinai
Aarthi Ramakrishnan: Icahn School of Medicine at Mount Sinai
Jennifer C Chan: Icahn School of Medicine at Mount Sinai
Bulent Cetin: Icahn School of Medicine at Mount Sinai
Erin Flaherty: Icahn School of Medicine at Mount Sinai
Li Shen: Icahn School of Medicine at Mount Sinai
Kelly Gleason: University of Texas Southwestern Medical School
Carol A. Tamminga: University of Texas Southwestern Medical School
Benjamin A. Garcia: University of Pennsylvania
Haitao Li: Tsinghua University
Kristen J. Brennand: Icahn School of Medicine at Mount Sinai
Ian Maze: Icahn School of Medicine at Mount Sinai

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29922-0

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