Cerebral ischemic stroke is one of the foremost global causes of death and disability. Due to inadequate knowledge in its sequential disease mechanisms, therapeutic efforts to mitigate acute ischemia-induced brain injury are limited. Recent studies have implicated epigenetic mechanisms, mostly histone lysine acetylation/deacetylation, in ischemia-induced neural damage and death. However, the role of lysine methylation/demethylation, another prevalent epigenetic mechanism in cerebral ischemia has not undergone comprehensive investigation, except a few recent reports, including those from our research cohort. Considering the impact of sex on post-stroke outcomes, we studied both male and female mice to elucidate molecular details using our recently developed Internal Carotid Artery Occlusion (ICAO) model, which induces mild to moderate cerebral ischemia, primarily affecting the striatum and ventral hippocampus. Here, we demonstrate for the first time that female mice exhibit faster recovery than male mice following ICAO, evaluated through neurological deficit score and motor coordination assessment. Furthermore, our investigation unveiled that dysregulated histone lysine demethylases (KDMs), particularly kdm4b/jmjd2b are responsible for the sex-specific variance in the modulation of inflammatory genes. Building upon our prior reportage blocking KDMs by DMOG (Dimethyloxalylglycine) and thus preventing the attenuation in H3k9me2 reduced the post-ICAO transcript levels of the inflammatory molecules and neural damage, our present study delved into investigating the differential role of H3k9me2 in the regulation of pro-inflammatory genes in female vis-à-vis male mice underlying ICAO-induced neural damage and recovery. Overall, our results reveal the important role of epigenetic mark H3k9me2 in mediating sex-specific sequential events in inflammatory response, elicited post-ICAO.

Graphical Abstract

中文翻译：

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揭示 H3k9me2 在颈内动脉闭塞小鼠模型神经炎症、损伤和恢复中的性别特异性表观遗传调控机制

脑缺血性中风是全球死亡和残疾的最重要原因之一。由于对其连续疾病机制了解不足，减轻急性缺血引起的脑损伤的治疗努力受到限制。最近的研究表明表观遗传机制（主要是组蛋白赖氨酸乙酰化/脱乙酰化）与缺血引起的神经损伤和死亡有关。然而，除了最近的一些报告（包括我们的研究队列的报告）外，赖氨酸甲基化/去甲基化（脑缺血中另一种常见的表观遗传机制）的作用尚未经过全面的研究。考虑到性别对中风后结局的影响，我们研究了雄性和雌性小鼠，以使用我们最近开发的颈内动脉闭塞（ICAO）模型来阐明分子细节，该模型会诱发轻度至中度脑缺血，主要影响纹状体和腹侧海马。在这里，我们首次证明，通过神经缺陷评分和运动协调评估进行评估，雌性小鼠在 ICAO 治疗后表现出比雄性小鼠更快的恢复速度。此外，我们的研究揭示了失调的组蛋白赖氨酸去甲基酶（KDM），特别是 kdm4b/jmjd2b 是导致炎症基因调节中性别特异性差异的原因。基于我们之前通过 DMOG（二甲基乙二酰甘氨酸）阻断 KDM 的报道，从而防止 H3k9me2 的减弱，降低了炎症分子和神经损伤的后 ICAO 转录水平，我们目前的研究深入研究了 H3k9me2 在调节前炎症反应中的不同作用。 - 雌性小鼠相对于雄性小鼠的炎症基因是国际民航组织诱导的神经损伤和恢复的基础。总的来说，我们的结果揭示了表观遗传标记 H3k9me2 在介导国际民航组织后引发的炎症反应中性别特异性序列事件中的重要作用。

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