The Dynamic Landscape of Open Chromatin during Human Cortical Neurogenesis

Luis de la Torre-Ubieta; Jason L Stein; Hyejung Won; Carli K Opland; Dan Liang; Daning Lu; Daniel H Geschwind

doi:10.1016/j.cell.2017.12.014

The Dynamic Landscape of Open Chromatin during Human Cortical Neurogenesis

Cell. 2018 Jan 11;172(1-2):289-304.e18. doi: 10.1016/j.cell.2017.12.014. Epub 2018 Jan 4.

Authors

Luis de la Torre-Ubieta¹, Jason L Stein², Hyejung Won¹, Carli K Opland¹, Dan Liang³, Daning Lu¹, Daniel H Geschwind⁴

Affiliations

¹ Neurogenetics Program, Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Neurogenetics Program, Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
³ Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
⁴ Neurogenetics Program, Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Center for Autism Research and Treatment, Semel Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: dhg@mednet.ucla.edu.

Abstract

Non-coding regions comprise most of the human genome and harbor a significant fraction of risk alleles for neuropsychiatric diseases, yet their functions remain poorly defined. We created a high-resolution map of non-coding elements involved in human cortical neurogenesis by contrasting chromatin accessibility and gene expression in the germinal zone and cortical plate of the developing cerebral cortex. We link distal regulatory elements (DREs) to their cognate gene(s) together with chromatin interaction data and show that target genes of human-gained enhancers (HGEs) regulate cortical neurogenesis and are enriched in outer radial glia, a cell type linked to human cortical evolution. We experimentally validate the regulatory effects of predicted enhancers for FGFR2 and EOMES. We observe that common genetic variants associated with educational attainment, risk for neuropsychiatric disease, and intracranial volume are enriched within regulatory elements involved in cortical neurogenesis, demonstrating the importance of this early developmental process for adult human cognitive function.

Keywords: ATAC-seq; chromatin; enhancers; evolution; human neocortical development; transcription factors.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Line
Cells, Cultured
Cerebral Cortex / cytology
Cerebral Cortex / embryology
Cerebral Cortex / metabolism*
Chromatin / genetics
Chromatin / metabolism
Chromatin Assembly and Disassembly*
Enhancer Elements, Genetic
Female
Gene Expression Regulation, Developmental*
Humans
Male
Neurogenesis*
Neurons / cytology
Neurons / metabolism*
Polymorphism, Genetic
Receptor, Fibroblast Growth Factor, Type 2 / genetics
Receptor, Fibroblast Growth Factor, Type 2 / metabolism
T-Box Domain Proteins / genetics
T-Box Domain Proteins / metabolism

Substances

Chromatin
EOMES protein, human
T-Box Domain Proteins
FGFR2 protein, human
Receptor, Fibroblast Growth Factor, Type 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding