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

Ruifen Wei1, Qianqian Chen1, Qinxiang Zheng1

  • 1State Key Laboratory of Ophthalmology, Optometry and Vision Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Ocular Immunology and Inflammation
|May 10, 2023
PubMed
Abstract

Insights

Circadian clock genes PER2 and PER3 are upregulated in experimental dry eye (EDE) disease. DNA methylation drives this increase, contributing to inflammation in EDE.

Area of Science:

  • Ophthalmology
  • Molecular Biology
  • Chronobiology

Background:

  • Dry eye disease (DED) is a prevalent ocular surface condition.
  • Inflammation plays a critical role in the pathogenesis of DED.
  • The involvement of circadian clock genes in DED-associated inflammation is not well understood.

Purpose of the Study:

  • To investigate the role of circadian clock genes in the inflammatory processes of experimental dry eye (EDE).

Main Methods:

  • Established a mouse model of EDE using an intelligently controlled environmental system (ICES).
  • Analyzed gene expression using RNA sequencing, RT-qPCR, and Western blot.
  • Assessed promoter methylation of Per genes using MethylTarget™ assays.
  • Utilized in vitro knockdown of Per2 and Per3 to evaluate their impact on inflammatory factors.

Main Results:

  • EDE model exhibited significant upregulation of circadian rhythm-associated genes.
  • PER2 and PER3 showed time-dependent upregulation and promoter hypomethylation during EDE.
  • Knockdown of PER2 or PER3 reduced inflammatory factor expression in vitro.
  • Silencing PER2/PER3 reversed inflammation in an azacitidine-treated in vitro model.

Conclusions:

  • Circadian clock genes PER2 and PER3 are implicated in EDE pathogenesis.
  • DNA methylation mediates the upregulation of PER2 and PER3 in EDE.
  • Targeting PER2 and PER3 may offer a therapeutic strategy for dry eye disease.
Keywords:
Circadian clock genesDNA methylationPER2dry eyeinflammation

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