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

The extensive heterogeneity of microglia inflammatory states accompanying neurodegenerative diseases underscores the complex molecular mechanisms that regulate these cells. 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. Therefore, distinct configuration of transcriptional input cooperate with epigenetic mechanisms to specify microglial inflammatory states and functions.