1. Human microglia maturation is underpinned by specific gene regulatory networks.
- Author
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Han, Claudia, Li, Rick, Hansen, Emily, Trescott, Samantha, Fixsen, Bethany, Nguyen, Celina, Mora, Cristina, Spann, Nathanael, Bennett, Hunter, Poirion, Olivier, Buchanan, Justin, Warden, Anna, Xia, Bing, Schlachetzki, Johannes, Pasillas, Martina, Preissl, Sebastian, Wang, Allen, OConnor, Carolyn, Shriram, Shreya, Kim, Roy, Schafer, Danielle, Ramirez, Gabriela, Challacombe, Jean, Anavim, Samuel, Johnson, Avalon, Gupta, Mihir, Glass, Ian, Levy, Michael, Haim, Sharona, Gonda, David, Laurent, Louise, Hughes, Jennifer, Page, David, Blurton-Jones, Mathew, Glass, Christopher, and Coufal, Nicole
- Subjects
epigenomics ,humanized ,microglia ,neurodevelopment ,neurological disorders ,stem cells ,transcription factors ,transcriptomics ,Humans ,Mice ,Animals ,Microglia ,Gene Regulatory Networks ,Brain ,Induced Pluripotent Stem Cells ,Gene Expression Regulation - Abstract
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.
- Published
- 2023