A human-specific enhancer modulates chromosomal interactions to promote neurogenesis [mouse RNA-seq]

Changes to the human genome have driven the evolution of human features including a larger neocortex and enhanced cognition. Human Accelerated Regions (HARs) are highly-conserved loci containing human-specific variants, which can be transcriptional enhancers during neurodevelopment. However, the neurodevelopmental functions of HARs and their mechanism of gene regulation are still largely unknown. Here, we show that the HAR1984 promotes neural progenitor cell identity and neurogenesis by influencing species-specific transcription and chromatin interactions. Humanized HAR1984 knock-in of chimpanzee cortical organoids increased intermediate progenitors and neurons, whereas chimpanzee HAR1984 knock-in in human cortical organoids produced the opposite phenotype. Moreover, humanized HAR1984 knock-in mouse brains showed increased progenitor proliferation and neuron number, resulting in a thicker cortex with cortical folding. Hi-C data revealed a chromatin loop of HAR1984 with its target genes, ETV5 and TRA2B, present in human fetal brains, but reduced in chimpanzee, macaque or mouse neural cells. We show that human-specific mutations in HAR1984 promote chromatin looping and that human-specific ETV5 binding auto-regulates enhancer activity. This work demonstrates new molecular mechanisms underlying human-specific neurodevelopment, linking HARs to chromatin architecture, cortical cell identity and evolutionary expansion of human brains.