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; Ian Maze

doi:10.1038/s41467-022-29922-0

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, Ian Maze

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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.

Original language	English (US)
Article number	2195
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-29922-0
State	Published - Dec 2022

ASJC Scopus subject areas

General
Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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10.1038/s41467-022-29922-0

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Farrelly, L. A., Zheng, S., Schrode, N., Topol, A., Bhanu, N. V., Bastle, R. M., Ramakrishnan, A., Chan, J. C., Cetin, B., Flaherty, E., Shen, L., Gleason, K., Tamminga, C. A., Garcia, B. A., Li, H., Brennand, K. J., & Maze, I. (2022). Chromatin profiling in human neurons reveals aberrant roles for histone acetylation and BET family proteins in schizophrenia. Nature communications, 13(1), [2195]. https://doi.org/10.1038/s41467-022-29922-0

Farrelly, LA, Zheng, S, Schrode, N, Topol, A, Bhanu, NV, Bastle, RM, Ramakrishnan, A, Chan, JC, Cetin, B, Flaherty, E, Shen, L, Gleason, K, Tamminga, CA, Garcia, BA, Li, H, Brennand, KJ & Maze, I 2022, 'Chromatin profiling in human neurons reveals aberrant roles for histone acetylation and BET family proteins in schizophrenia', Nature communications, vol. 13, no. 1, 2195. https://doi.org/10.1038/s41467-022-29922-0

@article{66bcf2b491ef4e449d2b45858f4bfc2b,

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

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 {\textquoteleft}reader{\textquoteright} 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.",

author = "Farrelly, {Lorna A.} and Shuangping Zheng and Nadine Schrode and Aaron Topol and Bhanu, {Natarajan V.} and Bastle, {Ryan M.} and Aarthi Ramakrishnan and Chan, {Jennifer C.} and Bulent Cetin and Erin Flaherty and Li Shen and Kelly Gleason and Tamminga, {Carol A.} and Garcia, {Benjamin A.} and Haitao Li and Brennand, {Kristen J.} and Ian Maze",

note = "Funding Information: We would like to thank members of the Maze, Brennand and Li laboratories for critical readings of the manuscript. We thank the staff members at beamline BL17U of the Shanghai Synchrotron Radiation Facility and the China National Center for Protein Sciences Beijing for providing facility support. This work was partially supported by grants from the National Institutes of Health: P50 MH096890 (I.M.), R01 HD097088 (I.M.), R01 MH116900 (I.M.), K99 MH120334 (L.A.F.), R01 AI118891 (B.A.G.), P01 CA196539 (B.A.G.), R56 MH101454 (K.J.B.), R01 MH106056 (K.J.B.) as well as awards from: (1) MQ Mental Health Research Charity, MQ15FIP100011 (I.M.), (2) Alfred P. Sloan Foundation Fellowship in Neuroscience (I.M.), (3) One Mind Institute (I.M.), (4) Brain and Behavior Research Foundation (L.A.F.), (5) the New York Stem Cell Foundation (K.J.B.) and (6) the National Natural Science Foundation of China (91753203 and 31725014, H.L.). Funding Information: We would like to thank members of the Maze, Brennand and Li laboratories for critical readings of the manuscript. We thank the staff members at beamline BL17U of the Shanghai Synchrotron Radiation Facility and the China National Center for Protein Sciences Beijing for providing facility support. This work was partially supported by grants from the National Institutes of Health: P50 MH096890 (I.M.), R01 HD097088 (I.M.), R01 MH116900 (I.M.), K99 MH120334 (L.A.F.), R01 AI118891 (B.A.G.), P01 CA196539 (B.A.G.), R56 MH101454 (K.J.B.), R01 MH106056 (K.J.B.) as well as awards from: (1) MQ Mental Health Research Charity, MQ15FIP100011 (I.M.), (2) Alfred P. Sloan Foundation Fellowship in Neuroscience (I.M.), (3) One Mind Institute (I.M.), (4) Brain and Behavior Research Foundation (L.A.F.), (5) the New York Stem Cell Foundation (K.J.B.) and (6) the National Natural Science Foundation of China (91753203 and 31725014, H.L.). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-29922-0",

language = "English (US)",

volume = "13",

journal = "Nature Communications",

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T1 - Chromatin profiling in human neurons reveals aberrant roles for histone acetylation and BET family proteins in schizophrenia

AU - Farrelly, Lorna A.

AU - Zheng, Shuangping

AU - Schrode, Nadine

AU - Topol, Aaron

AU - Bhanu, Natarajan V.

AU - Bastle, Ryan M.

AU - Ramakrishnan, Aarthi

AU - Chan, Jennifer C.

AU - Cetin, Bulent

AU - Flaherty, Erin

AU - Shen, Li

AU - Gleason, Kelly

AU - Tamminga, Carol A.

AU - Garcia, Benjamin A.

AU - Li, Haitao

AU - Brennand, Kristen J.

AU - Maze, Ian

N1 - Funding Information: We would like to thank members of the Maze, Brennand and Li laboratories for critical readings of the manuscript. We thank the staff members at beamline BL17U of the Shanghai Synchrotron Radiation Facility and the China National Center for Protein Sciences Beijing for providing facility support. This work was partially supported by grants from the National Institutes of Health: P50 MH096890 (I.M.), R01 HD097088 (I.M.), R01 MH116900 (I.M.), K99 MH120334 (L.A.F.), R01 AI118891 (B.A.G.), P01 CA196539 (B.A.G.), R56 MH101454 (K.J.B.), R01 MH106056 (K.J.B.) as well as awards from: (1) MQ Mental Health Research Charity, MQ15FIP100011 (I.M.), (2) Alfred P. Sloan Foundation Fellowship in Neuroscience (I.M.), (3) One Mind Institute (I.M.), (4) Brain and Behavior Research Foundation (L.A.F.), (5) the New York Stem Cell Foundation (K.J.B.) and (6) the National Natural Science Foundation of China (91753203 and 31725014, H.L.). Funding Information: We would like to thank members of the Maze, Brennand and Li laboratories for critical readings of the manuscript. We thank the staff members at beamline BL17U of the Shanghai Synchrotron Radiation Facility and the China National Center for Protein Sciences Beijing for providing facility support. This work was partially supported by grants from the National Institutes of Health: P50 MH096890 (I.M.), R01 HD097088 (I.M.), R01 MH116900 (I.M.), K99 MH120334 (L.A.F.), R01 AI118891 (B.A.G.), P01 CA196539 (B.A.G.), R56 MH101454 (K.J.B.), R01 MH106056 (K.J.B.) as well as awards from: (1) MQ Mental Health Research Charity, MQ15FIP100011 (I.M.), (2) Alfred P. Sloan Foundation Fellowship in Neuroscience (I.M.), (3) One Mind Institute (I.M.), (4) Brain and Behavior Research Foundation (L.A.F.), (5) the New York Stem Cell Foundation (K.J.B.) and (6) the National Natural Science Foundation of China (91753203 and 31725014, H.L.). Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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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JO - Nature Communications

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ER -

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

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