Won Hyejung, de la Torre-Ubieta Luis, Stein Jason L, Parikshak Neelroop N, Huang Jerry, Opland Carli K, Gandal Michael J, Sutton Gavin J, Hormozdiari Farhad, Lu Daning, Lee Changhoon, Eskin Eleazar, Voineagu Irina, Ernst Jason, Geschwind Daniel H
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.
Nature. 2016 Oct 27;538(7626):523-527. doi: 10.1038/nature19847. Epub 2016 Oct 19.
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.
染色体内部的三维物理相互作用以组织特异性方式动态调节基因表达。然而，人类大脑发育过程中染色体的三维组织及其在调节神经发育障碍（如自闭症或精神分裂症）中失调的基因网络中的作用尚不清楚。在这里，我们生成了人类皮质发生过程中染色质接触的高分辨率三维图谱，从而能够对与人类认知和疾病进化相关的先前未表征的调控关系进行大规模注释。我们的分析确定了数百个与人类谱系中获得的增强子发生物理相互作用的基因，其中许多基因处于纯化选择之下，并与人类认知功能相关。我们将染色质接触与精神分裂症全基因组关联研究（GWAS）中鉴定的非编码变异整合在一起，突出了多个候选精神分裂症风险基因和途径，包括参与神经发生的转录因子和胆碱能信号分子，其中一些得到了独立的表达数量性状位点和基因表达分析的支持。在人类神经祖细胞中进行的基因组编辑表明，这些远端精神分裂症GWAS位点之一调节FOXG1的表达，支持其作为精神分裂症风险基因的潜在作用。这项工作为理解非编码调控元件对人类大脑发育和认知进化的影响提供了一个框架，并突出了神经精神疾病的新机制。
