X chromosome escapee genes are involved in ischemic sexual dimorphism through epigenetic modification of inflammatory signals.
X chromosome escapee genes are involved in ischemic sexual dimorphism through epigenetic modification of inflammatory signals.
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X染色体逃逸基因通过炎症信号的表观遗传修饰参与缺血性两性二态性。
DOI：
10.1186/s12974-021-02120-3
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发表时间：
2021-03-12
影响因子：
9.3
通讯作者：
Liu F
中科院分区：
文献类型：
--
作者：
Qi S;Al Mamun A;Ngwa C;Romana S;Ritzel R;Arnold AP;McCullough LD;Liu F
中风是一种两性异形疾病。以前的研究发现，与男性相比，年轻女性对缺血的保护作用，部分原因是卵巢激素的保护作用，特别是雌激素（E2）。然而，X染色体剂量也存在遗传和表观遗传效应，导致中风敏感性和损伤后的神经炎症，特别是在老年人中。逃避X染色体失活（XCI）的基因导致许多疾病的性别特异性表型。Kdm 5c和kdm 6a是分别使H3 K4 me 3和H3 K27 me 3去甲基化的X逃逸基因。我们假设这两个去甲基化酶在介导中风敏感性中起关键作用。为了鉴定涉及中风的X逃逸基因，我们在来自经历大脑中动脉闭塞（MCAO）的老年雄性和雌性野生型（WT）小鼠的流式分选的小胶质细胞中进行了RNA-seq。这些基因（kdm 5c/kdm 6a）的表达，证实了在四个核心基因型（FCG）小鼠和死后的人类中风脑组织的免疫组织化学（IHC），蛋白质印迹，和RT-PCR。进行染色质免疫沉淀（ChIP）测定以检测由组蛋白H3 K4和H3 K27抗体沉淀的炎性干扰素调节因子（IRF）4/5的DNA水平。在小胶质细胞培养物中用siRNA或慢病毒操纵kdm 5c/kdm 6a表达，以确定下游途径并检查炎症细胞因子产生中的调节作用。老年WT雌性小胶质细胞中Kdm 5c和kdm 6a mRNA水平显著高于雄性小胶质细胞，并且在FCG小鼠和人类中风患者的缺血脑中也存在性别差异。ChIP测定显示，在雌性与雄性缺血性小胶质细胞中，IRF 4/5分别与去甲基化H3 K4或H3 K27具有更高的结合水平。用siRNA或慢病毒敲低或过表达kdm 5c/kdm 6a改变了IRF 4/5基因处H3 K4或H3 K27的甲基化，这反过来影响了炎性细胞因子的产生。提示KDM-组蛋白-IRF通路介导脑缺血的性别差异。脑卒中相关基因的表观遗传修饰是脑缺血性两性异形的重要机制。在线版本包含补充材料，可通过10.1186/s12974-021-02120-3获得。
Stroke is a sexually dimorphic disease. Previous studies have found that young females are protected against ischemia compared to males, partially due to the protective effect of ovarian hormones, particularly estrogen (E2). However, there are also genetic and epigenetic effects of X chromosome dosage that contribute to stroke sensitivity and neuroinflammation after injury, especially in the aged. Genes that escape from X chromosome inactivation (XCI) contribute to sex-specific phenotypes in many disorders. Kdm5c and kdm6a are X escapee genes that demethylate H3K4me3 and H3K27me3, respectively. We hypothesized that the two demethylases play critical roles in mediating the stroke sensitivity. To identify the X escapee genes involved in stroke, we performed RNA-seq in flow-sorted microglia from aged male and female wild type (WT) mice subjected to middle cerebral artery occlusion (MCAO). The expression of these genes (kdm5c/kdm6a) were confirmed in four core genotypes (FCG) mice and in post-mortem human stroke brains by immunohistochemistry (IHC), Western blot, and RT-PCR. Chromatin immunoprecipitation (ChIP) assays were conducted to detect DNA levels of inflammatory interferon regulatory factor (IRF) 4/5 precipitated by histone H3K4 and H3K27 antibodies. Manipulation of kdm5c/kdm6a expression with siRNA or lentivirus was performed in microglial culture, to determine downstream pathways and examine the regulatory roles in inflammatory cytokine production. Kdm5c and kdm6a mRNA levels were significantly higher in aged WT female vs. male microglia, and the sex difference also existed in ischemic brains from FCG mice and human stroke patients. The ChIP assay showed the IRF 4/5 had higher binding levels to demethylated H3K4 or H3K27, respectively, in female vs. male ischemic microglia. Knockdown or over expression of kdm5c/kdm6a with siRNA or lentivirus altered the methylation of H3K4 or H3K27 at the IRF4/5 genes, which in turn, impacted the production of inflammatory cytokines. The KDM-Histone-IRF pathways are suggested to mediate sex differences in cerebral ischemia. Epigenetic modification of stroke-related genes constitutes an important mechanism underlying the ischemic sexual dimorphism. The online version contains supplementary material available at 10.1186/s12974-021-02120-3.
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DOI：
10.1111/ejn.13778
发表时间：
2018-01
期刊：
The European journal of neuroscience
影响因子：
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作者：
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