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

被引：23

作者：

Farrelly, Lorna A. ^{[1
]}

Zheng, Shuangping ^{[2
]}

Schrode, Nadine ^{[3
]}

Topol, Aaron ^{[4
]}

Bhanu, Natarajan, V ^{[5
]}

Bastle, Ryan M. ^{[1
]}

Ramakrishnan, Aarthi ^{[1
]}

Chan, Jennifer C. ^{[1
]}

Cetin, Bulent ^{[1
]}

Flaherty, Erin ^{[1
,3
]}

Shen, Li ^{[1
]}

Gleason, Kelly ^{[6
]}

Tamminga, Carol A. ^{[6
]}

Garcia, Benjamin A. ^{[5
]}

Li, Haitao ^{[2
]}

Brennand, Kristen J. ^{[1
,3
,7
,8
,11
,12
]}

Maze, Ian ^{[1
,9
,10
]}

机构：

[1] Icahn Sch Med Mt Sinai, Friedman Brain Inst, Nash Family Dept Neurosci, New York, NY 10029 USA

[2] Tsinghua Univ, Beijing Adv Innovat Ctr Struct Biol, Sch Med, Dept Basic Med Sci,MOE Key Lab Prot Sci, Beijing 100084, Peoples R China

[3] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, Pamela Sklar Div Psychiat Genom, New York, NY 10029 USA

[4] Icahn Sch Med Mt Sinai, Grad Sch Biomed Sci, New York, NY 10029 USA

[5] Univ Penn, Perelman Sch Med, Epigenet Inst, Dept Biochem & Biophys, Philadelphia, PA 19104 USA

[6] Univ Texas Southwestern, Dept Psychiat, Med Sch, Dallas, TX 75390 USA

[7] Icahn Sch Med Mt Sinai, Black Family Stem Cell Inst, New York, NY 10029 USA

[8] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA

[9] Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, New York, NY 10029 USA

[10] Icahn Sch Med Mt Sinai, Howard Hughes Med Inst, New York, NY 10029 USA

[11] Yale Sch Med, Wu Tsai Inst, Dept Psychiat, New Haven, CT 06510 USA

[12] Yale Sch Med, Wu Tsai Inst, Dept Genet, New Haven, CT 06510 USA

来源：

NATURE COMMUNICATIONS | 2022年 / 13卷 / 01期

基金：

中国国家自然科学基金; 美国国家卫生研究院;

关键词：

BIPOLAR DISORDER; BRD1; GENE; METHYLATION; INHIBITION; CELLS; H2A.Z;

D O I：

10.1038/s41467-022-29922-0

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：10

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