Open chromatin landscape of rat microglia upon proinvasive or inflammatory polarization

Abstract

Microglia are brain‐resident, myeloid cells that play important roles in health and brain pathologies. Herein, we report a comprehensive, replicated, false discovery rate‐controlled dataset of DNase‐hypersensitive (DHS) open chromatin regions for rat microglia. We compared the open chromatin landscapes in untreated primary microglial cultures and cultures stimulated for 6\u2009hr with either glioma‐conditioned medium (GCM) or lipopolysaccharide (LPS). Glioma‐secreted factors induce proinvasive and immunosuppressive activation of microglia, and these cells then promote tumor growth. The open chromatin landscape of the rat microglia consisted of 126,640 reproducible DHS regions, among which 2,303 and 12,357 showed a significant change in openness following stimulation with GCM or LPS, respectively. Active genes exhibited constitutively open promoters, but there was no direct dependence between the aggregated openness of DHS regions near a gene and its expression. Individual regions mapped to the same gene often presented different patterns of openness changes. GCM‐regulated DHS regions were more frequent in areas away from gene bodies, while LPS‐regulated regions were more frequent in introns. GCM and LPS differentially affected the openness of regions mapped to immune checkpoint genes. The two treatments differentially affected the aggregated openness of regions mapped to genes in the Toll‐like receptor signaling and axon guidance pathways, suggesting that the molecular machinery used by migrating microglia is similar to that of growing axons and that modulation of these pathways is instrumental in the induction of proinvasive polarization of microglia by glioma. Our dataset of open chromatin regions paves the way for studies of gene regulation in rat microglia.