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Nature. 2016 Oct 27;538(7626):523-527. doi: 10.1038/nature19847. Epub 2016 Oct 19.

Chromosome conformation elucidates regulatory relationships in developing human brain.

Author information

  • 1Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, California 90095, USA.
  • 2Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, California 90095, USA.
  • 3School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
  • 4Department of Computer Science, University of California Los Angeles, California 90095, USA.
  • 5Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, California 90095, USA.
  • 6Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, California 90095, USA.

Abstract

Three-dimensional physical interactions within chromosomes dynamically regulate gene expression in a tissue-specific manner. 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 schizophrenia, 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.

PMID:
27760116
DOI:
10.1038/nature19847
[PubMed - in process]
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