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Epigenomic Study of Brain Development Uncovers Cell Type-Specific Regulatory Programs

NEW YORK – A team led by University of California, San Francisco researchers has teased out a range of 3D regulatory features behind the distinct transcriptional features found in several cell types in the developing human brain's cortex region.

"Our findings provide insights into cell type-specific gene expression patterns in the developing human cortex and advance our understanding of gene regulation and lineage specification during this crucial developmental window," corresponding authors Yin Shen, Arnold Kriegstein of UCSF, and  Ming Hu of the Cleveland Clinic Foundation, and their colleagues wrote in Nature on Wednesday.

The team noted that more than two-dozen brain subtypes turned up in a prior single-cell RNA sequencing-based analysis of the brain's dorsal cortex region, underscoring the wide range of cell types, regulatory features, and gene expression programs that are likely at play across the human brain during the process of corticogenesis.

For the new epigenome study, the researchers used cell sorting, RNA sequencing, proximity ligation-assisted chromatin immunoprecipitation sequencing, ATAC-seq, and other methods to take a look at the gene expression profiles, open chromatin regions, and chromatin interactions in the developing human cortex at a mid-gestational stage. Those analyses focused on several cell types, including radial glia, intermediate progenitor cells, excitatory neurons, and interneurons, in an effort to spell out cell-type specific regulatory features.

"By isolating and characterizing specific cell types, we are able to distinguish nuanced regulatory programs that drive cell type-specific differences during human corticogenesis," the authors explained.

Their findings pointed to gene regulation related to chromatin interactions, including long-range, cell type-specific chromatin interactions with apparent ties to transposable elements or to variants that have been previously implicated in disease risk.

"We show that chromatin interactions underlie several aspects of gene regulation, with transposable elements and disease-associated variants enriched at distal interacting regions in a cell type-specific manner," they explained.

The team also highlighted so-called "super-interactive promoters" in the developing brain cell types considered, which not only had higher-than-usual chromatin interaction levels, but also tended to interact with lineage-specific genes. From these and other findings, the authors speculated that the super-interactive promoters and the sites they interact with in the genome "contribute to the fine-tuning of transcription."

Drawing on regulatory clues from the brain cell types profiled, the investigators went on to develop a screening approach called CRISPRview for assessing cell type-specific regulatory element features in heterogeneous primary cell populations using a combination of CRISPR -based gene editing and interference, RNAscope probing, immunostaining, and other approaches.

"Future experiments using CRISPRview in live tissues should continue to reveal regulatory relationships in a manner that is truly representative of the complex in vivo environment," the authors concluded.