Chromatin domain alterations linked to 3D genome organization in a large cohort of schizophrenia and bipolar disorder brains.

Autor: Girdhar K; Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. kiran.girdhar@mssm.edu.; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. kiran.girdhar@mssm.edu.; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA. kiran.girdhar@mssm.edu., Hoffman GE; Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Bendl J; Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Rahman S; Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Dong P; Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Liao W; New York Genome Center, New York, NY, USA., Hauberg ME; Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Sloofman L; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Brown L; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Devillers O; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Kassim BS; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Wiseman JR; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Park R; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Zharovsky E; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Jacobov R; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Flatow E; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Kozlenkov A; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Gilgenast T; Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA., Johnson JS; Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Couto L; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Peters MA; Sage Bionetworks, Seattle, WA, USA., Phillips-Cremins JE; Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA., Hahn CG; Department of Psychiatry, Vickie and Jack Farber Institute for Neuroscience, Jefferson University, Philadelphia, PA, USA., Gur RE; Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, USA., Tamminga CA; Department of Psychiatry, The University of Texas Southwestern Medical School, Dallas, TX, USA., Lewis DA; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA., Haroutunian V; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Mental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, NY, USA., Dracheva S; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Mental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, NY, USA., Lipska BK; Human Brain Collection Core, National Institute of Mental Health-Intramural Research Program, Bethesda, MD, USA., Marenco S; Human Brain Collection Core, National Institute of Mental Health-Intramural Research Program, Bethesda, MD, USA., Kundakovic M; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Biological Sciences, Fordham University, Bronx, NY, USA., Fullard JF; Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Jiang Y; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China., Roussos P; Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. panagiotis.roussos@mssm.edu.; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. panagiotis.roussos@mssm.edu.; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA. panagiotis.roussos@mssm.edu.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. panagiotis.roussos@mssm.edu.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. panagiotis.roussos@mssm.edu.; Mental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, NY, USA. panagiotis.roussos@mssm.edu.; Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA. panagiotis.roussos@mssm.edu., Akbarian S; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. schahram.akbarian@mssm.edu.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. schahram.akbarian@mssm.edu.; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. schahram.akbarian@mssm.edu.
Jazyk: angličtina
Zdroj: Nature neuroscience [Nat Neurosci] 2022 Apr; Vol. 25 (4), pp. 474-483. Date of Electronic Publication: 2022 Mar 24.
DOI: 10.1038/s41593-022-01032-6
Abstrakt: 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, 10 4 -10 6 -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.
(© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE