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Chromosome conformation elucidates regulatory relationships in developing human brain

Nature volume 538, pages 523527 (27 October 2016) | Download Citation


Three-dimensional physical interactions within chromosomes dynamically regulate gene expression in a tissue-specific manner1,2,3. However, the 3D organization of chromosomes during human brain development and its role in regulating gene networks dysregulated in neurodevelopmental disorders, such as autism or schizophrenia4,5,6, are unknown. Here we generate high-resolution 3D maps of chromatin contacts during human corticogenesis, permitting large-scale annotation of previously uncharacterized regulatory relationships relevant to the evolution of human cognition and disease. Our analyses identify hundreds of genes that physically interact with enhancers gained on the human lineage, many of which are under purifying selection and associated with human cognitive function. We integrate chromatin contacts with non-coding variants identified in schizophrenia genome-wide association studies (GWAS), highlighting multiple candidate schizophrenia risk genes and pathways, including transcription factors involved in neurogenesis, and cholinergic signalling molecules, several of which are supported by independent expression quantitative trait loci and gene expression analyses. Genome editing in human neural progenitors suggests that one of these distal schizophrenia GWAS loci regulates FOXG1 expression, supporting its potential role as a schizophrenia risk gene. This work provides a framework for understanding the effect of non-coding regulatory elements on human brain development and the evolution of cognition, and highlights novel mechanisms underlying neuropsychiatric disorders.

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Gene Expression Omnibus

Data deposits

Sequencing data from this study have been deposited in the Gene Expression Omnibus and dbGaP under the accession number GSE77565 and phs001190.v1.p1, respectively.


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This work is a component of the psychENCODE project and was supported by NIH grants to D.H.G. (5R01MH060233; 5R01MH100027; 3U01MH103339; 1R01MH110927; 1R01MH094714), F.H. and E.E. (R01MH101782; R01ES022282; T32MH073526), J.L.S. (K99MH102357), and J.E. (R01ES024995), NSF CAREER Award (#1254200) to J.E., Glenn/AFAR Postdoctoral Fellowship Program (20145357) and Basic Science Research Program through the National Research Foundation of Korea (2013024227) to H.W., CIRM- BSCRC Training Grant (TG2-01169) to L.T.U., NRSA Training Grant to N.N.P. (F30MH099886; UCLA MSTP), NHMRC project grant (APP1062510) and ARC DECRA fellowship (DE140101033) to I.V. The Hi-C library was sequenced by the BSCRC, and fetal tissue was collected from the UCLA Center for Aids Research (CFAR, 5P30 AI028697). Schizophrenia RNA-seq data were generated as part of the CommonMind Consortium (see Methods and Supplementary Information). eQTL data was provided by M. Ryten and A. Ramasamy. We thank S. Feng, Y. Tian, V. Swarup, and P. S. Mischel for helpful discussions and critical reading of the manuscript.

Author information

Author notes

    • Jason L. Stein

    Present address: Department of Genetics & Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.


  1. Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, California 90095, USA

    • Hyejung Won
    • , Luis de la Torre-Ubieta
    • , Jason L. Stein
    • , Jerry Huang
    • , Carli K. Opland
    • , Michael J. Gandal
    • , Daning Lu
    • , Changhoon Lee
    •  & Daniel H. Geschwind
  2. Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, California 90095, USA

    • Neelroop N. Parikshak
    •  & Daniel H. Geschwind
  3. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia

    • Gavin J. Sutton
    •  & Irina Voineagu
  4. Department of Computer Science, University of California Los Angeles, California 90095, USA

    • Farhad Hormozdiari
    • , Eleazar Eskin
    •  & Jason Ernst
  5. Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, California 90095, USA

    • Eleazar Eskin
    •  & Daniel H. Geschwind
  6. Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, California 90095, USA

    • Jason Ernst


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H.W. designed and performed the Hi-C experiments, implemented the analysis pipeline, interpreted results of Hi-C and performed integration with other expression and epigenetic data, and co-wrote the manuscript. L.T.U., C.O., D.L. and J.H. performed sample collection, brain dissection, and genome editing experiments. J.L.S. and N.N.P. contributed to integrative and statistical analysis. M.J.G. analysed the schizophrenia transcriptomic data. G.J.S. and I.V. performed eRNA–mRNA correlation analyses. F.H. and E.E. aided in the implementation of CAVIAR for credible SNP selection and interpretation of the data. C.L. helped establish the initial Hi-C protocol. J.E. aided in the integration and interpretation of epigenetic data, and edited the manuscript. D.H.G. supervised the experimental design and analysis, interpreted results, provided funding, and co-wrote the manuscript.

Corresponding author

Correspondence to Daniel H. Geschwind.

Reviewer Information Nature thanks D. Goldstein, B. Ren and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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    Supplementary Information

    This file contains the legends for Supplementary Tables 1-27 (see separate excel file) and Supplementary Notes.

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    Supplementary Tables

    This file contains Supplementary Tables 1-27.

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