Publications

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

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.

PMID: 35332326 DOI: 10.1038/s41593-022-01032-6
Nat Neuroscience 2022 Mar 24.

Authors

Other Contributors

Kiran Girdhar 1 2 3, Gabriel E Hoffman 4 5 6, Jaroslav Bendl 4 5 6 7 8, Samir Rahman 4 5 6 7 8, Pengfei Dong 4 5 6 7 8, Will Liao 9, Mads E Hauberg 4 5 7 8 10 11, Laura Sloofman 12, Leanne Brown 7, Olivia Devillers 7, Bibi S Kassim 7, Jennifer R Wiseman 7, Royce Park 7, Elizabeth Zharovsky 7, Rivky Jacobov 7, Elie Flatow 7, Alexey Kozlenkov 8, Thomas Gilgenast 13, Jessica S Johnson 4 5 6, Lizette Couto 7, Mette A Peters 14, Jennifer E Phillips-Cremins 13, Chang-Gyu Hahn 15, Raquel E Gur 16, Carol A Tamminga 17, David A Lewis 18, Vahram Haroutunian 7 8 19 20, PsychENCODE Consortium; Stella Dracheva 7 8 20, Barbara K Lipska 21, Stefano Marenco 21, Marija Kundakovic 7 8 19 22, John F Fullard 4 5 6 7 8, Yan Jiang 7 8 19 23, Panos Roussos # 24 25 26 27 28 29 30, Schahram Akbarian # 31 32 33

 

  • 1Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 2Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 3Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 4Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 5Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 6Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 7Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 8Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 9New York Genome Center, New York, NY, USA.
  • 10iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.
  • 11Department of Biomedicine, Aarhus University, Aarhus, Denmark.
  • 12Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 13Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA.
  • 14Sage Bionetworks, Seattle, WA, USA.
  • 15Department of Psychiatry, Vickie and Jack Farber Institute for Neuroscience, Jefferson University, Philadelphia, PA, USA.
  • 16Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
  • 17Department of Psychiatry, The University of Texas Southwestern Medical School, Dallas, TX, USA.
  • 18Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
  • 19Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 20Mental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, NY, USA.
  • 21Human Brain Collection Core, National Institute of Mental Health-Intramural Research Program, Bethesda, MD, USA.
  • 22Department of Biological Sciences, Fordham University, Bronx, NY, USA.
  • 23Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.
  • 24Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 25Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 26Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 27Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 28Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 29Mental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, NY, USA.
  • 30Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
  • 31Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 32Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 33Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
#Contributed equally.

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