Markenscoff-Papadimitriou, E.

bioRxiv2022

Autism-associated transcriptional regulators target shared loci proximal to brain-expressed genes.

Many autism spectrum disorder (ASD)-associated genes act as transcriptional regulators (TRs). ChIP-seq was used to identify the regulatory targets of ARID1B, BCL11A, FOXP1, TBR1, and TCF7L2, ASD-associated TRs in the developing human and mouse cortex. These TRs shared substantial overlap in the binding sites, especially within open chromatin. The overlap within a promoter region, 1-2,000bp upstream of transcription start site, was highly predictive of brain expressed genes. This signature was observed at 96 out of 102 ASD-associated genes. In vitro CRISPRi against ARID1B and TBR1 delineated downstream convergent biology in mouse cortical cultures. After eight days, NeuN+ and CALB+ cells were decreased, GFAP+ cells were increased, and transcriptomic signatures correlated with the postmortem brain samples from individuals with ASD. We suggest functional convergence across five ASD-associated TRs leads to shared neurodevelopmental outcomes of haploinsufficient disruption.

genomics↗

bioRxiv2019

A Chromatin Accessibility Atlas of the Developing Human Telencephalon

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 functional 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.\n\nSummaryTo 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.

neuroscience↗