Abstract
During mammalian development, differences in chromatin state coincide with cellular differentiation and reflect changes in the gene regulatory landscape1. In the developing brain, cell fate specification and topographic identity are important for defining cell identity2 and confer selective vulnerabilities to neurodevelopmental disorders3. Here, to identify cell-type-specific chromatin accessibility patterns in the developing human brain, we used a single-cell assay for transposase accessibility by sequencing (scATAC-seq) in primary tissue samples from the human forebrain. We applied unbiased analyses to identify genomic loci that undergo extensive cell-type- and brain-region-specific changes in accessibility during neurogenesis, and an integrative analysis to predict cell-type-specific candidate regulatory elements. We found that cerebral organoids recapitulate most putative cell-type-specific enhancer accessibility patterns but lack many cell-type-specific open chromatin regions that are found in vivo. Systematic comparison of chromatin accessibility across brain regions revealed unexpected diversity among neural progenitor cells in the cerebral cortex and implicated retinoic acid signalling in the specification of neuronal lineage identity in the prefrontal cortex. Together, our results reveal the important contribution of chromatin state to the emerging patterns of cell type diversity and cell fate specification and provide a blueprint for evaluating the fidelity and robustness of cerebral organoids as a model for cortical development.
Highlights
Chromatin state defines the functional architecture of the genome by modulating the accessibility of gene regulatory elements, such as enhancers, which serve as binding sites for transcriptional regulators
At E12.5, embryos have an average crown-rump length of 8.6 mm. i, Enrichment and depletion of peaks that overlap with promoter-interacting regions[21], cell-type-specific peaks, and peaks that meet both criteria in copy number variant (CNV) regions enriched in children with NDD30 (n = 70 neurodevelopmental delay (NDD)-associated CNVs; Fisher’s exact, two-sided, P < 0.05)
We profiled the chromatin state of single cells in the developing human brain and found thousands of transiently accessible loci that track with neuronal differentiation
Summary
End, we intersected cell-type-specific ATAC-seq peaks and putative enhancers with disease-linked common and rare non-coding variants (Methods). We first intersected cell-type-specific peak sets, predicted enhancers, and peaks that overlapped promoter-interacting regions[21] with genomic regions that were enriched for copy number variants in individuals with developmental delay[30]; we identified significant enrichment in dlEN, endothelial/mural, and microglia-specific peaks, as well as peaks that overlapped promoter-interacting regions in a PFC. We intersected our cell-type-specific peak sets and predicted enhancers with de novo non-coding mutations (DNMs) identified from individuals with ASD and NDD, but no peak sets were significantly enriched for the currently annotated DNMs in a
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