Proliferating microglia integrate regulation of a core set of cell cycle genes with broader, context-dependent transcriptional programs

We report on the epigenomic and transcriptional programs associated with microglial proliferation in the brain. Gene expression profiles and genomic regulatory elements activity were determined on a genome-wide level. Data indicated that while the overall transcriptional out of proliferating microglia is context-dependent, a core signature of cell cycle genes accompanies proliferation across conditions. Furthermore, expression of these may be coordinated by one of two modes of regulation. A first mode augments expression of genes already expressed in quiescent microglia and is subject to regulation by Klf/Sp, Nfy, and Ets transcription factors. Alternatively, a second mode enables de novo gene transcription and requires additional regulatory input from Lin54 and E2f factors. Overall design: Proliferating microglia were isolated from various contexts, and their H3K27ac (ChIP-seq) and gene expression (RNA-seq) profiles were compared. Additional analyses with H3K4me3 (ChIP-seq), RNA polymerase II subunit B (ChIP-seq) and ATAC-seq were also performed to characterize the underlying regulatory mechanisms at the chromatin level.