3D-epigenome of Glial Cell Types in Developing Human Cortex

"The human cortex is complex and heterogeneous, undergoing extensive expansion during development. Our study of neurogenesis, including radial glia (RG), intermediate progenitor cells (IPCs), excitatory neurons (eNs), and interneurons (iN) demonstrated that chromatin looping underlies transcriptional regulation for lineage-specific genes, shedding insight on how non-coding genetic variants contribute to neuropsychiatric disorders via cell type-specific gene regulation. Radial glia play a crucial role in generating cellular diversity through both neurogenesis and gliogenesis and can be further classified into ventricular radial glia (vRG) and outer radial glia (oRG). Given their significance in cortical development, we conducted a comprehensive 3D epigenomic analysis of four major glial populations, including vRG, oRG, oligodendrocyte precursor cells (OPC), and microglia (MG), from the mid-gestational human neocortex. By integrating gene expression, chromatin accessibility, DNA methylation, and 3D chromatin interactions, we identified cell type-specific candidate cis-regulatory elements (cCREs) and validated their enhancer function using transgenic mouse embryos. Using machine learning, we prioritized 112 schizophrenia risk variants within glia cCREs and further confirmed the predicted vRG enhancer disruption by rs4449074 risk allele in vivo. Finally, oRG cCREs are enriched for human accelerated regions (HARs) compared to other cCREs and a subset of HARs have predicted activity differences compared to their chimpanzee orthologs that interact with genes involved in neuronal development. Our findings advance the understanding of human-specific gene regulation during corticogenesis."

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