H3K4 METHYLATION SELECTIVELY PROMOTES BASAL PROGENITOR PROLIFERATION AND NEOCORTEX EXPANSION BY ACTIVATING ZFHX4 EXPRESSION

Cortical neurogenesis during embryonic stages provides the developmental foundation that underpins the functional architecture of the mammalian brain. Compared with rodents, the human cerebral cortex displays increased gyrification and surface area, a feature thought to arise from the enhanced proliferative capacity of basal progenitors (BPs) during evolution. Emerging evidence suggests that such evolutionary changes may be driven, at least in part, by epigenetic modifications in BPs; however, the nature and extent of epigenomic differences between human and non-human BPs remain poorly understood. Here, we report that histone H3 lysine 4 methylation (H3K4me) represents a key epigenetic mechanism regulating neural progenitor proliferation and differentiation in both mouse and human developing cortex. Using fluorescence-activated cell sorting combined with mass spectrometry–based epigenetic profiling, we identify a striking interspecies difference in H3K4 methylation levels, with murine BPs exhibiting significantly lower H3K4me compared with their human counterparts. Functionally, elevated H3K4me prolongs the neurogenic window and enhances BP proliferation, resulting in increased cortical size and the emergence of cortical convolutions in the otherwise lissencephalic mouse neocortex. Mechanistically, increased H3K4me promotes BP amplification through the upregulation of the evolutionarily regulated gene Zfhx4 in the developing cortex. These discoveries shed light on a previously undemonstrated mechanism that contributes to the regulation of mammalian cortical development and evolutionary expansion.