Genome-wide chromosomal conformation elucidates regulatory relationships in human brain development and disease

The demonstration that chromatin exhibits a complex 3 dimensional organization, whereby short and long distance physical interactions correspond to complex gene regulatory processes has opened a new window on understanding the functional organization of the human genome. Recently, chromatin remodeling has also been causally implicated in several neurodevelopmental disorders, including autism and schizophrenia. However, it remains unclear whether knowledge of chromosome organization in a tissue specific manner might inform our understanding of gene regulation in brain development or disease. Here we determined the genome-wide landscape of chromosome conformation during early human cortical development by performing Hi-C analysis in the mitotically active and post mitotic laminae of human fetal brain. We integrate Hi-C data with transcriptomic and epigenomic data and utilize chromosome contact information to delineate physical gene-gene regulatory interactions for non-coding regulatory elements. We show how these data permit large-scale functional annotation of non-coding variants identified in schizophrenia GWAS and of human specific enhancers. These data provide a rubric that illustrates the power of tissue-specific annotation of non-coding regulatory elements, as well as novel insights into the pathogenic mechanisms of neurodevelopmental disorders and the evolution of higher cognition.