Gene regulatory networks underlying human microglia maturation [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA941262 | ENA |
REPOSITORIES: ENA
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2023-08-14 | GSE226705 | GEO
Project description: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.
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Project description:As tissue macrophages of the central nervous system (CNS), microglia are critically involved in diseases of the CNS. However, it remains unknown what controls their maturation and activation under homeostatic conditions. Here we reveal significant contributions of the host microbiota to microglia homeostasis as germ-free (GF) mice displayed global defects in microglia with altered cell proportions and an immature phenotype leading to impaired innate immune responses. Temporal eradication of host microbiota severely changed microglia properties. Limited microbiota complexity also resulted in defective microglia. In contrast, recolonization with a complex microbiota partially restored microglia features. We determined that short-chain fatty acids (SCFA), microbiota-derived bacterial fermentation products, regulate microglia homeostasis. Accordingly, mice deficient for the SCFA receptor FFAR2 mirrored microglia defects found under GF conditions. These findings reveal that host bacteria vitally regulate microglia maturation and function, whereas microglia impairment can be restored to some extent by complex microbiota. We used microarrays to determine the gene expression of microglia after LCMV challenge. Lymphocytic Choriomeningitis Virus (LCMV) strain WE was propagated and titrated as plaque forming units (PFU) on L929 cells as described before (Herz,J. et al. Acid sphingomyelinase is a key regulator of cytotoxic granule secretion by primary T lymphocytes. Nat. Immunol. 10, 761-768 (2009)). PFU were multiplied by the factor 10 to be converted into infectious units (IU). Mice were infected by intracerebral inoculation of 103 IU into the right hemisphere.
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