Chromosome conformation elucidates regulatory relationships in developing human brain

Hyejung Won, Luis de la Torre-Ubieta, Jason L. Stein, Neelroop N. Parikshak, Jerry Huang, Carli K. Opland, Michael J. Gandal, Gavin J. Sutton, Farhad Hormozdiari, Daning Lu, Changhoon Lee, Eleazar Eskin, Irina Voineagu, Jason Ernst and Daniel H. Geschwind ()
Additional contact information
Hyejung Won: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles
Luis de la Torre-Ubieta: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles
Jason L. Stein: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles
Neelroop N. Parikshak: Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California Los Angeles
Jerry Huang: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles
Carli K. Opland: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles
Michael J. Gandal: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles
Gavin J. Sutton: School of Biotechnology and Biomolecular Sciences, University of New South Wales
Farhad Hormozdiari: University of California Los Angeles
Daning Lu: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles
Changhoon Lee: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles
Eleazar Eskin: University of California Los Angeles
Irina Voineagu: School of Biotechnology and Biomolecular Sciences, University of New South Wales
Jason Ernst: University of California Los Angeles
Daniel H. Geschwind: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles

Nature, 2016, vol. 538, issue 7626, 523-527

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/nature19847

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