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

Author

Listed:
  • 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
    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
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Ian Maze

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

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.

Suggested Citation

  • 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 Gleas, 2022. "Chromatin profiling in human neurons reveals aberrant roles for histone acetylation and BET family proteins in schizophrenia," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29922-0
    DOI: 10.1038/s41467-022-29922-0
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    References listed on IDEAS

    as
    1. Ángeles Gómez-Zambrano & Wiam Merini & Myriam Calonje, 2019. "The repressive role of Arabidopsis H2A.Z in transcriptional regulation depends on AtBMI1 activity," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    2. Kristen J. Brennand & Anthony Simone & Jessica Jou & Chelsea Gelboin-Burkhart & Ngoc Tran & Sarah Sangar & Yan Li & Yangling Mu & Gong Chen & Diana Yu & Shane McCarthy & Jonathan Sebat & Fred H. Gage, 2011. "Erratum: Modelling schizophrenia using human induced pluripotent stem cells," Nature, Nature, vol. 479(7374), pages 556-556, November.
    3. Panagis Filippakopoulos & Jun Qi & Sarah Picaud & Yao Shen & William B. Smith & Oleg Fedorov & Elizabeth M. Morse & Tracey Keates & Tyler T. Hickman & Ildiko Felletar & Martin Philpott & Shonagh Munro, 2010. "Selective inhibition of BET bromodomains," Nature, Nature, vol. 468(7327), pages 1067-1073, December.
    4. Kristen J. Brennand & Anthony Simone & Jessica Jou & Chelsea Gelboin-Burkhart & Ngoc Tran & Sarah Sangar & Yan Li & Yangling Mu & Gong Chen & Diana Yu & Shane McCarthy & Jonathan Sebat & Fred H. Gage, 2011. "Modelling schizophrenia using human induced pluripotent stem cells," Nature, Nature, vol. 473(7346), pages 221-225, May.
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    Cited by:

    1. Gianluca Ursini & Pasquale Di Carlo & Sreya Mukherjee & Qiang Chen & Shizhong Han & Jiyoung Kim & Maya Deyssenroth & Carmen J. Marsit & Jia Chen & Ke Hao & Giovanna Punzi & Daniel R. Weinberger, 2023. "Prioritization of potential causative genes for schizophrenia in placenta," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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