@article{f7913bcb83324ca39312bf0044868c64,
title = "Chromatin domain alterations linked to 3D genome organization in a large cohort of schizophrenia and bipolar disorder brains",
abstract = "Chromosomal organization, scaling from the 147-base pair (bp) nucleosome to megabase-ranging domains encompassing multiple transcriptional units, including heritability loci for psychiatric traits, remains largely unexplored in the human brain. In this study, we constructed promoter- and enhancer-enriched nucleosomal histone modification landscapes for adult prefrontal cortex from H3-lysine 27 acetylation and H3-lysine 4 trimethylation profiles, generated from 388 controls and 351 individuals diagnosed with schizophrenia (SCZ) or bipolar disorder (BD) (n = 739). We mapped thousands of cis-regulatory domains (CRDs), revealing fine-grained, 104–106-bp chromosomal organization, firmly integrated into Hi-C topologically associating domain stratification by open/repressive chromosomal environments and nuclear topography. Large clusters of hyper-acetylated CRDs were enriched for SCZ heritability, with prominent representation of regulatory sequences governing fetal development and glutamatergic neuron signaling. Therefore, SCZ and BD brains show coordinated dysregulation of risk-associated regulatory sequences assembled into kilobase- to megabase-scaling chromosomal domains.",
author = "{PsychENCODE Consortium} and Kiran Girdhar and Hoffman, {Gabriel E.} and Jaroslav Bendl and Samir Rahman and Pengfei Dong and Will Liao and Hauberg, {Mads E.} and Laura Sloofman and Leanne Brown and Olivia Devillers and Kassim, {Bibi S.} and Wiseman, {Jennifer R.} and Royce Park and Elizabeth Zharovsky and Rivky Jacobov and Elie Flatow and Alexey Kozlenkov and Thomas Gilgenast and Johnson, {Jessica S.} and Lizette Couto and Peters, {Mette A.} and Phillips-Cremins, {Jennifer E.} and Hahn, {Chang Gyu} and Gur, {Raquel E.} and Tamminga, {Carol A.} and Lewis, {David A.} and Vahram Haroutunian and Stella Dracheva and Lipska, {Barbara K.} and Stefano Marenco and Marija Kundakovic and Fullard, {John F.} and Yan Jiang and Panos Roussos and Schahram Akbarian",
note = "Funding Information: We thank the late P. Sklar for many contributions in the early phase of this project and P. Rajarajan and S. Espeso-Gil for helpful discussions. This work was supported, in part, through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. We are extremely grateful to J. Ochando, C. Bare and other personnel of the Icahn School of Medicine at Mount Sinai{\textquoteright}s Flow Cytometry Core for providing and teaching cell-sorting expertise and to L. Bingman in the Division of Neuroscience and Basic Behavioral Science at the National Institute of Mental Health (National Institutes of Health (NIH)) for logistical support in the context of the PsychENCODE Consortium. This project was supported by NIH U01DA048279 (S.A. and P.R.) and R01MH106056 (S.A.). PsychENCODE Consortium: data were generated as part of the first phase of the PsychENCODE Consortium, supported by U01MH103339, U01MH103365, U01MH103392, U01MH103340, U01MH103346, R01MH105472, R01MH094714, R01MH105898, R21MH102791, R21MH105881, R21MH103877 and P50MH106934 awarded to S.A. (Icahn School of Medicine at Mount Sinai), G. Crawford (Duke University), S. Dracheva (Icahn School of Medicine at Mount Sinai), P. Farnham (University of Southern California (USC)), M. Gerstein (Yale University), D. Geschwind (University of California, Los Angeles), T. M. Hyde (Lieber Institute for Brain Development (LIBD)), A. Jaffe (LIBD), J. A. Knowles (USC), C. Liu (University of Illinois at Chicago), D. Pinto (Icahn School of Medicine at Mount Sinai), N. Sestan (Yale University), P. Sklar (Icahn School of Medicine at Mount Sinai), M. State (University of California, San Francisco), P. Sullivan (University of North Carolina), F. Vaccarino (Yale University), S. Weissman (Yale University), K. White (University of Chicago) and P. Zandi (Johns Hopkins Universityu). The HBCC is funded by the National Institute of Mental Health-Intramural Research Program through project ZIC MH002903. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Funding Information: The source data described in this manuscript are available via the PsychENCODE Knowledge Portal ( https://psychencode.synapse.org/ ). The PsychENCODE Knowledge Portal is a platform for accessing data, analyses and tools generated through grants funded by the National Institute of Mental Health PsychENCODE program. Data are available for general research use according to the following requirements for data access and data attribution: https://psychencode.synapse.org/DataAccess . Funding Information: We thank the late P. Sklar for many contributions in the early phase of this project and P. Rajarajan and S. Espeso-Gil for helpful discussions. This work was supported, in part, through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. We are extremely grateful to J. Ochando, C. Bare and other personnel of the Icahn School of Medicine at Mount Sinai{\textquoteright}s Flow Cytometry Core for providing and teaching cell-sorting expertise and to L. Bingman in the Division of Neuroscience and Basic Behavioral Science at the National Institute of Mental Health (National Institutes of Health (NIH)) for logistical support in the context of the PsychENCODE Consortium. This project was supported by NIH U01DA048279 (S.A. and P.R.) and R01MH106056 (S.A.). PsychENCODE Consortium: data were generated as part of the first phase of the PsychENCODE Consortium, supported by U01MH103339, U01MH103365, U01MH103392, U01MH103340, U01MH103346, R01MH105472, R01MH094714, R01MH105898, R21MH102791, R21MH105881, R21MH103877 and P50MH106934 awarded to S.A. (Icahn School of Medicine at Mount Sinai), G. Crawford (Duke University), S. Dracheva (Icahn School of Medicine at Mount Sinai), P. Farnham (University of Southern California (USC)), M. Gerstein (Yale University), D. Geschwind (University of California, Los Angeles), T. M. Hyde (Lieber Institute for Brain Development (LIBD)), A. Jaffe (LIBD), J. A. Knowles (USC), C. Liu (University of Illinois at Chicago), D. Pinto (Icahn School of Medicine at Mount Sinai), N. Sestan (Yale University), P. Sklar (Icahn School of Medicine at Mount Sinai), M. State (University of California, San Francisco), P. Sullivan (University of North Carolina), F. Vaccarino (Yale University), S. Weissman (Yale University), K. White (University of Chicago) and P. Zandi (Johns Hopkins Universityu). The HBCC is funded by the National Institute of Mental Health-Intramural Research Program through project ZIC MH002903. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2022",
month = apr,
doi = "10.1038/s41593-022-01032-6",
language = "English",
volume = "25",
pages = "474--483",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "4",
}