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<p>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 <i>Kdm6a</i> and <i>Kdm5c</i> are involved in microglial activation after stroke in aged mice. However, the underlying mechanisms remain unclear. We hypothesized that <i>Kdm6a/5c</i> 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&#xa0;months) <i>Kdm6a/5c</i> 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&#xa0;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 <i>IRF5/4</i> by Kdm6a/5c was analyzed by CUT&amp;RUN assay. The demethylation of H3K27Me3 by kdm6a increased <i>IRF5</i> transcription; meanwhile, Kdm5c demethylated H3K4Me3 to repress <i>IRF5</i>. Both <i>Kdm6a</i><sup>fl/fl</sup> and <i>Kdm5c</i><sup>fl/fl</sup> 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’<i>s</i> effect is independent of IRF5.</p>

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Escape of Kdm6a from X Chromosome Is Detrimental to Ischemic Brains via IRF5 Signaling

  • 期刊论文

  • 发表日期：

    2025年1月3日

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  • Conelius Ngwa,
  • Afzal Misrani,
  • Kanaka Valli Manyam,
  • Yan Xu,
  • Shaohua Qi,
  • Romana Sharmeen,
  • Juneyoung Lee,
  • Long-Jun Wu,
  • Louise McCullough,
  • Fudong Liu

摘要

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.