Multi-tier signaling and epigenomic reprogramming drive microglial inflammatory states and functions associated with demyelination [RNA-seq]

Here, we report on transcriptional effectors that control microglial inflammatory state polarization associated with brain demyelination in mice. Using flow cytometry, microscopy and RNA-seq, we identified two dominant, functionally distinct states of Clec7a+CD229+ inflammatory microglia, discriminated from one another by CD11c expression.

Epigenomic analyses implicated extensive genome-wide nucleosome remodeling to the polarization process, driven by state-associated stimulation of transcription factors that included Pu.1, AP-1, Bhlhe40 and Egr2, as well as re-calibration of homeostatic input provided by Mef2. Notably, a H3K27me3-based epigenetic gatekeeping mechanisms controls transcription of Egr2 and Bhlhe40 genes. Loss-of-function experiments validated the physiological relevance of Trem2, Mef2a and Egr2 to the microglial inflammatory state polarization process in the demyelinating brain.