Gene regulatory networks underlying human microglia maturation [RNA-seq]
Microglia, the tissue resident macrophages of the brain, are observed as early as the fourth week of human gestation and engage in a variety of processes essential for brain development and homeostasis. Microglia phenotypes are highly regulated by the brain environment but the transcriptional networks that specify their maturation remain poorly understood and the extent to which fetal or postnatal phenotypes can be modeled using iPSC-derived cells has not been systematically investigated. Here, we characterized stage-specific transcriptomes and epigenetic landscapes of fetal and postnatal human microglia ex vivo and acquired corresponding data in iPSC-derived microglia in vitro, in cerebral organoids, and as a function of time following engraftment into humanized mice.  By developing new computational approaches that integrate these data to predict state-specific transcription factor networks, we provide evidence that MiTF/TFE and MEF2 factors are key nodes in transcription factor networks associated with fetal microglia phenotypes, whereas MAFB, KLFs and IRF transcription factors are key nodes in the networks associated with postnatal phenotypes.  We further demonstrate that many features of the human fetal to postnatal transition in microglia gene expression are recapitulated in a time-dependent manner following the engraftment of iPSC-derived hematopoietic progenitor cells into humanized mice.  These studies thereby provide new computational and data resources enabling the elucidation of transcription factor networks underlying stage-specific human microglia phenotypes. Overall design: Poly-A RNA-seq and ATAC-seq of iPSC-derived microglia, iPSC-derived microglia co-cultured with cerebral organoids, and iHPC xenografted into humanized mice and isolated at various time points.