TY - JOUR
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 - 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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UR - http://www.scopus.com/inward/citedby.url?scp=85128784613&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-29922-0
DO - 10.1038/s41467-022-29922-0
M3 - Article
C2 - 35459277
AN - SCOPUS:85128784613
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2195
ER -