RT Journal Article
SR Electronic
T1 A Chromatin Accessibility Atlas of the Developing Human Telencephalon
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 811620
DO 10.1101/811620
A1 Eirene Markenscoff-Papadimitriou
A1 Sean Whalen
A1 Pawel Przytycki
A1 Reuben Thomas
A1 Fadya Binyameen
A1 Tomasz J. Nowakowski
A1 Stephan J. Sanders
A1 Matthew W. State
A1 Katherine S. Pollard
A1 John L. Rubenstein
YR 2019
UL http://biorxiv.org/content/early/2019/10/21/811620.abstract
AB Gene expression differs between cell types and regions within complex tissues such as the developing brain. To discover regulatory elements underlying this specificity, we generated genome-wide maps of chromatin accessibility in eleven anatomically-defined regions of the developing human telencephalon, including upper and deep layers of the prefrontal cortex. We predicted a subset of open chromatin regions (18%) that are most likely to be active enhancers, many of which are dynamic with 26% differing between early and late mid-gestation and 28% present in only one brain region. These region-specific predicted regulatory elements (pREs) are enriched proximal to genes with expression differences across regions and developmental stages and harbor distinct sequence motifs that suggest potential upstream regulators of regional and temporal transcription. We leverage this atlas to identify regulators of genes associated with autism spectrum disorder (ASD) including an enhancer of BCL11A, validated in mouse, and two de novo mutations in individuals with ASD in an enhancer of SLC6A1, validated in neuroblastoma cells. These applications demonstrate the utility of this atlas for decoding neurodevelopmental gene regulation in health and disease.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 eleven dissected regions of the mid-gestation human telencephalon, including 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 regional differences in chromatin accessibility, including many specific to one brain region, and were correlated with gene expression differences across the same regions and gestational ages. pREs allowed us to map neurodevelopmental disorder risk genes to developing telencephalic regions, and we identified three functional de novo noncoding variants in pREs that alter enhancer function. In addition, transgenic experiments in mouse validated enhancer activity for a pRE proximal to BCL11A, showing how this atlas serves as a resource for decoding neurodevelopmental gene regulation in health and disease.