BACH1 changes microglial metabolism and affects astrogenesis during mouse brain development.

Microglia are highly heterogeneous as resident immune cells in the central nervous system. Although the proinflammatory phenotype of microglia is driven by the metabolic transformation in the disease state, the mechanism of metabolic reprogramming in microglia and whether it affects surrounding astrocyte progenitors have not been well elucidated. Here, we illustrate the communication between microglial metabolism and astrogenesis during embryonic development. The transcription factor BTB and CNC homology 1 (Bach1) reduces lactate production by inhibiting two key enzymes, HK2 and GAPDH, during glycolysis. Metabolic perturbation of microglia reduces lactate-dependent histone modification enrichment at the Lrrc15 promoter. The microglia-derived LRRC15 interacts with CD248 to participate in the JAK/STAT pathway and influence astrogenesis. In addition, Bach1 cKO-Cx3 mice exhibit abnormal neuronal differentiation and anxiety-like behaviors. Altogether, this work suggests that the maintenance of microglia metabolic homeostasis during early brain development is closely related to astrogenesis, providing insights into astrogenesis and related diseases. [Display omitted] • Transcription factor Bach1 is essential for microglia metabolic homeostasis and histone lactylation • Decreased H4K12la levels in microglia reduce histone lactylation enrichment at the promoter of Lrrc15 • Microglia-derived LRRC15 participates in astrogenesis through the JAK/STAT pathway • Microglia Bach1 -deficient mice show anxiety-like behavior Wang and Wang et al. reported that BACH1 can orchestrate astrogenesis by influencing microglia metabolic homeostasis. Absence of BACH1 leads to decreased lactate-dependent histone modification at the Lrrc15 promoter, which affects astrogenesis through the CD248-JAK-STAT signaling pathway. [ABSTRACT FROM AUTHOR]