Details

Autor(en) / Beteiligte

• 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.

Titel

Chromosome conformation elucidates regulatory relationships in developing human brain

Ist Teil von

• Nature (London), 2016-10, Vol.538 (7626), p.523-527

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• Three-dimensional physical interactions within chromosomes dynamically regulate gene expression in a tissue-specific manner 1 , 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 schizophrenia 4 , 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. High-resolution three-dimensional maps of chromatin contacts in the developing human brain help to identify enhancer–promoter contacts, many of which are associated with human cognitive function and disease. Gene regulation in the developing brain Chromatin is organized into hierarchical three-dimensional structures that are thought to have a role in gene regulation by defining the functional units within which cis -regulatory elements interact with their target genes. Here, Daniel Geschwind and colleagues use the Hi-C technique to generate high-resolution three-dimensional maps of chromatin contacts in human developing brain. By integrating the Hi-C maps with other datasets they identify novel enhancer–promoter contacts, many of which are associated with human cognitive function. They also integrate these chromatin contact maps with non-coding variants identified in schizophrenia genome-wide association studies to propose novel candidate risk genes and pathways for schizophrenia.