title: Chromosome conformation elucidates regulatory relationships in developing human brain.
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.
authors.affiliation: Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, California 90095, USA.
authors.forename: Hyejung
authors.initials: H
authors.lastname: Won
authors.affiliation: Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, California 90095, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: de la Torre-Ubieta
authors.affiliation: Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, California 90095, USA.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Stein
authors.affiliation: Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, California 90095, USA.
authors.forename: Neelroop N
authors.initials: NN
authors.lastname: Parikshak
authors.affiliation: Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, California 90095, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, California 90095, USA.
authors.forename: Carli K
authors.initials: CK
authors.lastname: Opland
authors.affiliation: Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, California 90095, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gandal
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Gavin J
authors.initials: GJ
authors.lastname: Sutton
authors.affiliation: Department of Computer Science, University of California Los Angeles, California 90095, USA.
authors.forename: Farhad
authors.initials: F
authors.lastname: Hormozdiari
authors.affiliation: Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, California 90095, USA.
authors.forename: Daning
authors.initials: D
authors.lastname: Lu
authors.affiliation: Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, California 90095, USA.
authors.forename: Changhoon
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Computer Science, University of California Los Angeles, California 90095, USA.|Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, California 90095, USA.
authors.forename: Eleazar
authors.initials: E
authors.lastname: Eskin
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Irina
authors.initials: I
authors.lastname: Voineagu
authors.affiliation: Department of Computer Science, University of California Los Angeles, California 90095, USA.|Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, California 90095, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Ernst
authors.affiliation: Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, California 90095, USA.|Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, California 90095, USA.|Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, California 90095, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
mesh_terms: D001921:Brain / Q000196:embryology* / Q000378:metabolism*; D002843:Chromatin / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D002877:Chromosomes, Human / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D003071:Cognition; D004742:Enhancer Elements, Genetic / Q000235:genetics; D044127:Epigenesis, Genetic; D051858:Forkhead Transcription Factors / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics; D058953:Neural Stem Cells / Q000378:metabolism; D055495:Neurogenesis; D009690:Nucleic Acid Conformation; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D015203:Reproducibility of Results; D012559:Schizophrenia / Q000235:genetics / Q000473:pathology
chemical_list: D002843:Chromatin; C090173:FOXG1 protein, human; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins