Research findings reported in Nature offer novel insights into how the cerebral cortex forms in utero during the development of the nervous system (termed corticogenesis). Corticogenesis is a highly complex process that requires balancing of many components. Uncovering the interplay of these contributing components is critical to understanding diseases associated with dysfunctional cortical development, like neuropsychiatric diseases.
The interdisciplinary research team—including researchers from Cleveland Clinic; University of California, San Francisco (UCSF); Washington University in St. Louis; and University of North Carolina at Chapel Hill—sought to analyze cell types that are critical in the developing cortex. These included radial glia cells that differentiate to engender intermediate progenitor cells and further develop into excitatory neurons in the cortex, as well as interneurons that originate in the ventral cortex and migrate tangentially into the dorsal cortex.
This cell proliferation and differentiation (or lineage specification) is controlled in part by epigenetic changes—chemical modifications that affect gene expression and cellular function without actually modifying DNA sequence.
While previous studies have relied on single cell RNA sequencing to elucidate the extreme heterogeneity of the human brain, they did not offer a detailed understanding of the chromatin accessibility and spatial organization of individual cell types. This study has filled in this critical gap by jointly profiling all three levels of information.
“For the first time, we have identified the epigenetic calling cards of individual cell types critical for corticogenesis, which significantly advances our understanding of gene regulation and cell fate during human brain development,” said Ming Hu, PhD, a computational biologist who specializes in genetic and epigenetic studies in Cleveland Clinic Lerner Research Institute’s Department of Quantitative Health Sciences, and the co-first and co-corresponding author on the study.
Using a multi-omics approach, the researchers made several key discoveries related to lineage specification and gene expression. First, they found that gene regulation is closely linked to how chromatin folds in 3D space. More specifically, they found a very high degree of chromatin interactivity with a particular subset of gene promoters, which they term super-interactive promoters. These super-interactive promoters are enriched for lineage-specific genes, suggesting that interactions at these loci help to fine tune transcription.
Additionally, they showed that DNA sequences that have the ability to change their positions within a genome, called transposable elements, likely play an important role in sustaining gene expression.
Understanding these chromatin interactions can help researchers to prioritize relevant cell types and genetic variants associated with neuropsychiatric disorders, which can help inform which targets are worth investigating with follow-up functional experiments and can pave the way to new therapeutic targets.
Findings from this study, for example, show that genetic variants associated with autism spectrum disorder are the most enriched at distal cis-regulatory elements in excitatory neurons compared to the other cell types studied. Dr. Hu expanded, “This information can help determine precisely which genomic and epigenomic changes in which regions of the genome can be targeted for new treatments in disease-relevant cell types.”
Notably, this study relied heavily on a computational method developed by Dr. Hu’s team, called MAPS (Model-based Analysis of PLAC-seq data). Because of its high sensitivity, accuracy and robustness, MAPS is now the production pipeline for PLAC-seq data in the 4D Nucleome Project supported by the National Institutes of Health.
This study, which was a true collaborative effort, was supported in part by the National Institutes of Health and an Innovation Award from the UCSF Weill Institute for Neuroscience. Dr. Hu worked closely with genomicist Yin Shen, PhD, and neuroscientist Arnold Kriegstein, MD, PhD, both of UCSF and co-corresponding authors on the study; geneticist Ting Wang, PhD, Washington University in St. Louis; and statistical geneticist Yun Li, PhD, University of North Carolina at Chapel Hill.