A Chromatin Accessibility Atlas of the Developing Human Telencephalon

To discover regulatory elements driving the specificity of gene expression in different cell types and regions of the developing human brain, we generated an atlas of open chromatin from nine dissected regions of the mid-gestation human telencephalon, as well as microdissected upper and deep layers...

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Bibliographic Details
Published in:Cell 2020-08, Vol.182 (3), p.754-769.e18
Main Authors: Markenscoff-Papadimitriou, Eirene, Whalen, Sean, Przytycki, Pawel, Thomas, Reuben, Binyameen, Fadya, Nowakowski, Tomasz J., Kriegstein, Arnold R., Sanders, Stephan J., State, Matthew W., Pollard, Katherine S., Rubenstein, John L.
Format: Article
Language:English
Subjects:
Animals
ATAC-seq
autism
Autistic Disorder - genetics
Cell Line
chromatin
Chromatin - genetics
Chromatin - metabolism
Chromatin Immunoprecipitation Sequencing
Enhancer Elements, Genetic
enhancers
Euchromatin - genetics
GABA Plasma Membrane Transport Proteins - genetics
Gene Expression Regulation, Developmental - genetics
Gene Ontology
gene regulation
Genetic Predisposition to Disease
Gestational Age
Humans
machine learning
Mice
Mice, Transgenic
neurodevelopment
neuropsychiatric disorders
Nucleotide Motifs
Point Mutation
Prefrontal Cortex - embryology
Prefrontal Cortex - metabolism
Repressor Proteins - genetics
Repressor Proteins - metabolism
Spatio-Temporal Analysis
Telencephalon - embryology
Telencephalon - metabolism
Transcription Factors - genetics
Transcription Factors - metabolism
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Summary:To discover regulatory elements driving the specificity of gene expression in different cell types and regions of the developing human brain, we generated an atlas of open chromatin from nine dissected regions of the mid-gestation human telencephalon, as well as microdissected upper and deep layers of the prefrontal cortex. We identified a subset of open chromatin regions (OCRs), termed predicted regulatory elements (pREs), that are likely to function as developmental brain enhancers. pREs showed temporal, regional, and laminar differences in chromatin accessibility and were correlated with gene expression differences across regions and gestational ages. We identified two functional de novo variants in a pRE for autism risk gene SLC6A1, and using CRISPRa, demonstrated that this pRE regulates SCL6A1. Additionally, mouse transgenic experiments validated enhancer activity for pREs proximal to FEZF2 and BCL11A. Thus, this atlas serves as a resource for decoding neurodevelopmental gene regulation in health and disease. [Display omitted] •∼19,000 enhancers defined in nine regions of the developing human telencephalon•Chromatin dynamics correlate with sequence motifs and spatiotemporal gene expression•Identified cortical layer-specific enhancers and validated a layer 5 FEZF2 enhancer•Genetic variants from patients alter activity of an enhancer for an autism risk gene A high-resolution atlas of regulatory elements driving regional, temporal, and laminar gene expression programs in the developing human telencephalon reveals enhancers and genetic variants regulating human disease genes.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2020.06.002