TY - JOUR
T1 - Chromosome conformation elucidates regulatory relationships in developing human brain
AU - Won, Hyejung
AU - De La Torre-Ubieta, Luis
AU - Stein, Jason L.
AU - Parikshak, Neelroop N.
AU - Huang, Jerry
AU - Opland, Carli K.
AU - Gandal, Michael J.
AU - Sutton, Gavin J.
AU - Hormozdiari, Farhad
AU - Lu, Daning
AU - Lee, Changhoon
AU - Eskin, Eleazar
AU - Voineagu, Irina
AU - Ernst, Jason
AU - Geschwind, Daniel H.
N1 - Publisher Copyright:
© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84993993658&partnerID=8YFLogxK
U2 - 10.1038/nature19847
DO - 10.1038/nature19847
M3 - Article
C2 - 27760116
AN - SCOPUS:84993993658
SN - 0028-0836
VL - 538
SP - 523
EP - 527
JO - Nature
JF - Nature
IS - 7626
ER -