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

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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.

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Fig. 1: Histone peak profiling in 739 ChIP-seq datasets from two studies consisting of SCZ, BD and control subjects.
Fig. 2: Enrichment of common SCZ risk variants in dysregulated peaks in NeuN+ and bulk tissue.
Fig. 3: PFC histone CRDs reveal sub-TAD chromosomal organization.
Fig. 4: Acetylated CRDs dysregulated in SCZ.
Fig. 5: Fingerprinting disease-sensitive CRDs.
Fig. 6: Spatial organization of diseased CRDs in the virtual Chrom3D model of the neuronal nucleus.

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Data availability

Raw data (FASTQ files) and processed data (BigWig files, metadata, peaks and raw and normalized count matrices) have been deposited in Synapse under synID syn25705564. Browsable UCSC genome browser tracks of our processed ChIP-seq data are available as a resource at EpiDiff Phase 2 http://genome.ucsc.edu/s/girdhk01/EpiDiff_Phase2.

External validation sets used in the study are as follows: H3K27ac ChIP-seq fetal-specific peaks: spatio-temporal enrichment of H3K27ac peaks table from http://development.psychencode.org/#; RoadMap Epigenome Project H3K27ac, H3K4me3 tissue ChIP-seq peaks, chromHMM states on E073 and fetal male E081 and fetal female E082 (https://egg2.wustl.edu/roadmap/data/byFileType/chromhmmSegmentations/ChmmModels/coreMarks/jointModel/final/); and CTCF ChIP-seq on human neural cell (Gene Expression Omnibus GSE127577). TruSeq3-PE.fa file was downloaded from the adaptor folder under the Trimmomatic repository: https://github.com/timflutre/trimmomatic/blob/master/adapters/TruSeq3-PE.fa.

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.

Code availability

All publicly available software used is noted in the Methods. We used decorate software to call CRDs: https://github.com/GabrielHoffman/decorate.

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Acknowledgements

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’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.

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Author notes

  1. These authors contributed equally: Panos Roussos, Schahram Akbarian.

Authors and Affiliations

  1. Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Kiran Girdhar, Gabriel E. Hoffman, Jaroslav Bendl, Samir Rahman, Pengfei Dong, Mads E. Hauberg, Jessica S. Johnson, John F. Fullard & Panos Roussos

  2. Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Kiran Girdhar, Gabriel E. Hoffman, Jaroslav Bendl, Samir Rahman, Pengfei Dong, Mads E. Hauberg, Jessica S. Johnson, John F. Fullard & Panos Roussos

  3. Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Kiran Girdhar, Gabriel E. Hoffman, Jaroslav Bendl, Samir Rahman, Pengfei Dong, Jessica S. Johnson, John F. Fullard & Panos Roussos

  4. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jaroslav Bendl, Samir Rahman, Pengfei Dong, Mads E. Hauberg, Leanne Brown, Olivia Devillers, Bibi S. Kassim, Jennifer R. Wiseman, Royce Park, Elizabeth Zharovsky, Rivky Jacobov, Elie Flatow, Lizette Couto, Vahram Haroutunian, Stella Dracheva, Marija Kundakovic, John F. Fullard, Yan Jiang, Panos Roussos & Schahram Akbarian

  5. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jaroslav Bendl, Samir Rahman, Pengfei Dong, Mads E. Hauberg, Alexey Kozlenkov, Vahram Haroutunian, Stella Dracheva, Marija Kundakovic, John F. Fullard, Yan Jiang, Panos Roussos & Schahram Akbarian

  6. New York Genome Center, New York, NY, USA

    Will Liao

  7. iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark

    Mads E. Hauberg

  8. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Mads E. Hauberg

  9. Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Laura Sloofman

  10. Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA

    Thomas Gilgenast & Jennifer E. Phillips-Cremins

  11. Sage Bionetworks, Seattle, WA, USA

    Mette A. Peters

  12. Department of Psychiatry, Vickie and Jack Farber Institute for Neuroscience, Jefferson University, Philadelphia, PA, USA

    Chang-Gyu Hahn

  13. Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Raquel E. Gur

  14. Department of Psychiatry, The University of Texas Southwestern Medical School, Dallas, TX, USA

    Carol A. Tamminga

  15. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    David A. Lewis

  16. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Vahram Haroutunian, Marija Kundakovic, Yan Jiang & Schahram Akbarian

  17. Mental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, NY, USA

    Vahram Haroutunian, Stella Dracheva & Panos Roussos

  18. Human Brain Collection Core, National Institute of Mental Health-Intramural Research Program, Bethesda, MD, USA

    Barbara K. Lipska & Stefano Marenco

  19. Department of Biological Sciences, Fordham University, Bronx, NY, USA

    Marija Kundakovic

  20. Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China

    Yan Jiang

  21. Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA

    Panos Roussos

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  1. Kiran Girdhar
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  2. Gabriel E. Hoffman
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Consortia

PsychENCODE Consortium

Contributions

Wet lab work, including tissue processing, sorting of nuclei and ChIP-seq and Hi-C library generation: Y.J., L.B., M.K., E.Z., R.J., J.R.W., R.P., B.S.K., L.C., O.D., S.R., J.F., E.F. and A.K. Data processing and coordination: Y.J., M.K., M.A.P. and J.S.J. Bioinformatics and computational genomics: K.G., G.E.H., J.B., S.R., T.G., J.P.-C., P.D., W.L., M.E.H., L.S. and L.C. Provision of brain tissue and resources: C.A.T., S.M., B.K.L., D.A.L., V.H., C.-G.H., R.E.G., S.D. and P.C. Conception of study and design: P.R., S.A., K.G., G.E.H. and J.B. Writing of the paper: K.G., S.A. and P.R.

Corresponding authors

Correspondence to Kiran Girdhar, Panos Roussos or Schahram Akbarian.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Neuroscience thanks Angel Barco, Inge Holtman and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Captions for Supplementary Figs. 1–22

Reporting Summary

Supplementary Data 1

PsychENCODE members list

Supplementary Table 1

Metadata of samples in Study-1 and Study-2

Supplementary Table 2

Genomic coordinates of consensus peaks

Supplementary Table 3

Differential analysis of peaks across SCZ cases and controls and across BD cases and controls

Supplementary Table 4

GWAS enrichment of brain traits and non-brain-related traits in peaks stratified by differentially upregulated and downregulated peaks

Supplementary Table 5

Genomic coordinates of identified CRDs

Supplementary Table 6

Annotation and differential analysis of CRDs

Supplementary Table 7

Pathway analysis of ΔCRDΔPeaks

Supplementary Table 8

Genomic coordinates of H3K27ac GABA-, Glu- and OLIG-specific peaks

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Girdhar, K., Hoffman, G.E., Bendl, J. et al. Chromatin domain alterations linked to 3D genome organization in a large cohort of schizophrenia and bipolar disorder brains. Nat Neurosci 25, 474–483 (2022). https://doi.org/10.1038/s41593-022-01032-6

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