Epigenetic Activation of Circadian Clock Genes Elicits Inflammation in Experimental Murine Dry Eye.

IF 2.6 4区医学 Q2 OPHTHALMOLOGY Ocular Immunology and Inflammation Pub Date : 2024-09-01 Epub Date: 2023-05-10 DOI:10.1080/09273948.2023.2205525

Ruifen Wei, Qianqian Chen, Qinxiang Zheng, Peter S Reinach, Xiying Tan, Chengjie Pan, Wei Xu, Louis Tong, Wei Chen

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Abstract

Purpose: To explore whether circadian clock genes contribute to elicit inflammation in experimental dry eye (EDE).

Methods: RNA sequencing analyzed mRNA expression patterns in EDE model. RT-qPCR and/or Western blot determined the expression of inflammatory factors and circadian genes during EDE. MethylTarget™ assays determined the promoter methylation levels of Per genes in vivo. Per2 or Per3 knockdown assessed their effects on inflammatory factors in vitro.

Results: We utilized an intelligently controlled environmental system (ICES) to establish a mouse EDE model. The significant upregulated genes were enriched for circadian rhythms. Therein lied oscillatory and time-dependent upregulation of PER2 and PER3, as well as their promoter hypomethylation during EDE. Silencing PER2 or PER3 significantly decreased inflammatory factor expression and also reversed such increased inflammatory response in azacitidine (AZA) treatment in vitro model.

Conclusions: Our findings suggest that DNA methylation mediated the upregulation of PER2 and PER3, leading to inflammatory response in EDE.

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昼夜节律时钟基因的表观遗传激活引发实验性小鼠干眼症的炎症反应

目的：探讨昼夜节律时钟基因是否有助于引发实验性干眼症（EDE）的炎症：方法：RNA测序分析EDE模型中mRNA的表达模式。RT-qPCR和/或Western blot检测EDE过程中炎症因子和昼夜节律基因的表达。MethylTarget™ 检测确定了体内 Per 基因启动子甲基化水平。Per2或Per3基因敲除评估了它们对体外炎症因子的影响：我们利用智能控制环境系统（ICES）建立了小鼠 EDE 模型。显著上调的基因富含昼夜节律。在 EDE 期间，PER2 和 PER3 存在振荡和时间依赖性上调及其启动子低甲基化。在阿扎胞苷（AZA）治疗的体外模型中，沉默PER2或PER3可显著降低炎症因子的表达，并逆转这种炎症反应的增加：我们的研究结果表明，DNA甲基化介导了PER2和PER3的上调，导致了EDE中的炎症反应。

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来源期刊

Ocular Immunology and Inflammation 医学-眼科学

CiteScore

6.20

自引率

15.20%

发文量

285

审稿时长

6-12 weeks

期刊介绍： Ocular Immunology & Inflammation ranks 18 out of 59 in the Ophthalmology Category.Ocular Immunology and Inflammation is a peer-reviewed, scientific publication that welcomes the submission of original, previously unpublished manuscripts directed to ophthalmologists and vision scientists. Published bimonthly, the journal provides an international medium for basic and clinical research reports on the ocular inflammatory response and its control by the immune system. The journal publishes original research papers, case reports, reviews, letters to the editor, meeting abstracts, and invited editorials.

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