Evolution of regulatory signatures in primate cortical neurons at cell-type resolution [ChIP-Seq]

The human cerebral cortex contains many cell types that likely underwent independent functional changes during evolution. However, cell-type–specific regulatory landscapes in the cortex re- main largely unexplored. Here we report epigenomic and tran- scriptomic analyses of the two main cortical neuronal subtypes, glutamatergic projection neurons and GABAergic interneurons, in human, chimpanzee, and rhesus macaque. Using genome- wide profiling of the H3K27ac histone modification, we identify neuron-subtype–specific regulatory elements that previously went undetected in bulk brain tissue samples. Human-specific regula- tory changes are uncovered in multiple genes, including those as- sociated with language, autism spectrum disorder, and drug addiction. We observe preferential evolutionary divergence in neuron subtype-specific regulatory elements and show that a sub- stantial fraction of pan-neuronal regulatory elements undergos subtype-specific evolutionary changes. This study sheds light on the interplay between regulatory evolution and cell- type–dependent gene-expression programs, and provides a re- source for further exploration of human brain evolution and function. Overall design: ChIP-seq Histone 3 Lysine 27 acetylation (H3K27ac) profiling was performed on sorted nuclei of glutamatergic and MGE-derived GABAergic neurons, obtained from prefrontal cortex of chimpanzees, rhesus macaques and humans. Raw data (fastq) for human samples were taken from: Kozlenkov et al, 2018, Science Advances, 4(9):eaau6190