한빛사논문
- 조회3,820
Abstract
Hyejung Won1, Luis de la Torre-Ubieta1, Jason L. Stein1†, Neelroop N. Parikshak2, Jerry Huang1, Carli K. Opland1, Michael J. Gandal1, Gavin J. Sutton3, Farhad Hormozdiari4, Daning Lu1, Changhoon Lee1, Eleazar Eskin4,5, Irina Voineagu3, Jason Ernst4,6 & Daniel H. Geschwind1,2,5
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. †Present address: Department of Genetics & Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Correspondence to : Daniel H. Geschwind
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.
논문정보
- Research article
- 2016년 10월 (BRIC 등록일 2016-11-01)
- 국외 연구진
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