Human microglia maturation is underpinned by specific gene regulatory networks

Microglia phenotypes are highly regulated by the brain environment, but the transcriptional networks that specify the maturation of human microglia are poorly understood. Here, we characterized stage-specific transcriptomes and epigenetic landscapes of fetal and postnatal human microglia and acquired corresponding data in induced pluripotent stem cell (iPSC)-derived microglia, in cerebral organoids, and following engraftment into humanized mice. Parallel development of computational approaches that considered transcription factor (TF) co-occurrence and enhancer activity allowed prediction of shared and state-specific gene regulatory networks associated with fetal and postnatal microglia. Additionally, many features of the human fetal-to-postnatal transition were recapitulated in a time-dependent manner following the engraftment of iPSC cells into humanized mice. These data and accompanying computational approaches will facilitate further efforts to elucidate mechanisms by which human microglia acquire stage- and disease-specific phenotypes. [Display omitted] •Human microglia have unique developmental stage-dependent epigenomic landscapes•TIMON predicts transcription factor cooperativity in human microglia maturation•Transcriptomes and epigenomes inform interpretation of disease risk alleles•iPSC-derived microglia can model developmental stage-specific phenotypes Molecular mechanisms that drive human microglia diversity remain largely unknown. Han and Li et al. characterize transitions in the transcriptomes and epigenomes of human fetal and postnatal microglia, develop computational tools that predict underlying gene regulatory networks, and demonstrate that core features of these networks can be captured by iPSC-derived microglia.