3D Epigenome Evolution Underlies Divergent Gene Regulatory Programs in Primate Neural Development

The expansion of the neocortex is a hallmark of human evolution and is closely linked to neural stem cell biology. Yet, the epigenetic mechanisms driving divergent gene regulation during primate neurogenesis remain elusive. Here, we comprehensively mapped 3D genome organization, chromatin accessibility and gene expression in induced pluripotent stem cells and derived neural stem cells from human, chimpanzee, gorilla and macaque. We identified human-specific epigenetic signatures including cis-regulatory regions and enhancer-promoter interactions and linked them to gene regulatory dynamics. Deep learning models revealed that complex regulatory grammar at cis-regulatory regions, including transcription factor binding sites, local context and higher-order chromatin organization, underlies species and cell type-specific differences. High-resolution Hi-C uncovered unexpected global shifts in 3D genome architecture in chimpanzee and gorilla neural stem cells while topologically associating domains remain remarkably conserved. Notably, species-specific genes interacted with multiple differentially accessible regions, suggesting that synergistic enhancer activation is a key mechanism driving epigenome evolution. These findings provide new insights into the epigenetic basis of primate brain evolution.