Multi-tier signaling and chromatin remodeling coordinate microglia inflammatory states and activities associated with demyelination.

Complex molecular mechanisms underlie the heterogeneity of microglia immune functions in neurodegenerative diseases. Here, we report on the transcriptional mechanisms that control microglial activities associated with demyelination in mice. Using flow cytometry, microscopy, and RNA-seq, we identify two dominant states of inflammatory microglia: Clec7a+CD229+CD11c- microglia, which are prone to proliferation and express high mRNA levels of Fn1 and Vegfa, and Clec7a+CD229+CD11c+ microglia, which are characterized by prominent mRNA expression of tissue-remodeling and antigen presentation effectors. Achieving these states implicates genome-wide nucleosome remodeling, which is driven by state-dependent stimulation of transcription factors such as Pu.1, AP-1, C/ebp, Mef2, and Egr2. Notably, an H3K27me3-based gatekeeping mechanism controls expression of key regulators, including Egr2. Mechanistically, we validate the relevance of Trem2, Mef2a, and Egr2 to the inflammatory microglial polarization process. Therefore, distinct configurations of signals, along with chromatin remodeling, orchestrate transcription in microglia to support their immune activities in the context of demyelination.