Language
English
Publication Date
10-1-2025
Journal
Translational Stroke Research
DOI
10.1007/s12975-024-01321-1
PMID
39752046
PMCID
PMC12222549
PubMedCentral® Posted Date
7-3-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
The role of chromatin biology and epigenetics in disease progression is gaining increasing recognition. Genes that escape X chromosome inactivation (XCI) can impact neuroinflammation through epigenetic mechanisms. Our previous study has suggested that the X escapee genes Kdm6a and Kdm5c are involved in microglial activation after stroke in aged mice. However, the underlying mechanisms remain unclear. We hypothesized that Kdm6a/5c demethylate H3K27Me3/H3K4Me3 in microglia, respectively, and mediate the transcription of interferon regulatory factor 5 (IRF5) and IRF4, leading to microglial pro-inflammatory responses and exacerbated stroke injury. Aged (17–20 months) Kdm6a/5c microglial conditional knockout (CKO) female mice (one allele of the gene) were subjected to a 60-min middle cerebral artery occlusion (MCAO). Gene floxed females (two alleles) and males (one allele) were included as controls. Infarct volume and behavioral deficits were quantified 3 days after stroke. Immune responses including microglial activation and infiltration of peripheral leukocytes in the ischemic brain were assessed by flow cytometry. Epigenetic modification of IRF5/4 by Kdm6a/5c was analyzed by CUT&RUN assay. The demethylation of H3K27Me3 by kdm6a increased IRF5 transcription; meanwhile, Kdm5c demethylated H3K4Me3 to repress IRF5. Both Kdm6afl/fl and Kdm5cfl/fl mice had worse stroke outcomes compared to fl/y and CKO mice. Gene floxed females showed more robust expression of CD68 in microglia and elevated brain and plasma levels of IL-1β or TNF-α, after stroke. We concluded that IRF5 signaling plays a critical role in mediating the deleterious effect of Kdm6a, whereas Kdm5c’s effect is independent of IRF5.
Keywords
Animals, Interferon Regulatory Factors, Histone Demethylases, Mice, Female, Male, Signal Transduction, Mice, Knockout, Microglia, Brain Ischemia, X Chromosome, X Chromosome Inactivation, Mice, Inbred C57BL, Aging, Kdm6a/5c, Microglia, Epigenetics, Ischemia, IRF
Published Open-Access
yes
Recommended Citation
Ngwa, Conelius; Misrani, Afzal; Manyam, Kanaka Valli; et al., "Escape of Kdm6a from X Chromosome Is Detrimental to Ischemic Brains via IRF5 Signaling" (2025). The Brown Foundation: Institute of Molecular Medicine. 38.
https://digitalcommons.library.tmc.edu/molecular_med/38