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 hr 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.

Neuron-specific chromosomal megadomain organization is adaptive to recent retrotransposon expansions

“…In contrast, no pathway enrichment was observed for the group of 211 microglial genes downregulated in mutant cortex. Next, given that the microglial genomic response to inflammatory stimuli also involves widespread changes in chromatin accessibility 28 , we profiled open chromatin landscapes on a genome-wide scale using Assay for Transposase Accessible Chromatin (ATAC-seq) on CD11b-immunopanned microglia from mutant and control forebrain ( N = 3/group) (Fig. 5e , Data S18).…”

The role of epigenetic modifications, long-range contacts, enhancers and topologically associating domains in the regulation of glioma grade-specific genes

“…Chromatin openness, examined with DNAse I-seq or ATAC-seq assays, correlates positively with transcriptional activity 13 , 14 . Open chromatin—marked with H3K4me1 but depleted of H3K4me3, has been associated with enhancers 15 , 16 .…”

Ghrelin reduces cerebral ischemic injury in rats by reducing M1 microglia/macrophages

“…M1 can produce interleukin (IL)-1, IL-6, IL-23, tumor necrosis factor α (TNF-α) and other pro-inflammatory factors, as well as CCL2, CXCL9 and CXCL10 and other chemokines to promote inflammation and tissue damage, causing toxic effects on neurons. 6 M2 can secrete anti-inflammatory factors such as IL-4, IL-10 and transforming growth factor β, inhibit excessive inflammatory response, promote tissue repair and neuron regeneration, and promote vascular regeneration and tissue repair. 7 The environment of the infarct zone is conducive to the differentiation of macrophages into M1 type, further aggravating brain tissue damage.…”