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Epigenetic Modulation of Thyroid-Stimulating Hormone Receptor Expression in Orbital Fibroblasts From Graves'

Rajit Chompoowong1, Pimchanok Phankeaw1, Apinya Suwannavong1

  • 1Medical Microbiology, Interdisciplinary Program, Graduate School, Chulalongkorn University, Bangkok, Thailand.

Investigative Ophthalmology & Visual Science
|August 7, 2026
PubMed
Abstract

Insights

DNA methyltransferases (DNMTs) and EZH2 are key in Graves' ophthalmopathy (GO). DNMT1 is highly expressed in active GO and influences thyroid-stimulating hormone receptor (TSHR) and fibrotic markers, suggesting therapeutic potential.

Area of Science:

  • Endocrinology and Metabolism
  • Molecular Biology
  • Immunology

Background:

  • Graves' ophthalmopathy (GO) is an autoimmune condition affecting orbital tissues.
  • Thyroid-stimulating hormone receptor (TSHR) and fibrotic markers are implicated in GO pathogenesis.
  • Epigenetic regulators like DNA methyltransferases (DNMTs) and EZH2 may play a role in GO.

Purpose of the Study:

  • To investigate the expression and function of DNMTs and EZH2 in regulating TSHR and fibrotic markers in orbital fibroblasts from GO patients.
  • To explore the role of platelet-derived growth factor (PDGF)-BB in modulating DNMT expression.
  • To assess the therapeutic potential of inhibiting DNMTs and EZH2 in GO.

Main Methods:

  • Quantification of DNMT mRNA levels in orbital fibroblasts from healthy controls, active GO, and inactive GO (iGOF) patients.
  • Measurement of TSHR and fibrotic markers in iGOFs treated with PDGF-BB, decitabine (DNMT inhibitor), DZNep (EZH2 inhibitor), or small interfering RNA.
  • Techniques used include RT-qPCR and Western blotting.

Main Results:

  • DNMT1 and DNMT3A mRNA expressions were significantly elevated in active GO fibroblasts compared to inactive GO and control fibroblasts.
  • PDGF-BB stimulation induced DNMT1 and DNMT3A mRNA levels in iGOFs.
  • Decitabine and DNMT1 silencing inhibited PDGF-BB-induced cell viability and TSHR expression; EZH2 inhibition showed a similar, though less pronounced, effect.

Conclusions:

  • DNMT1 is the predominant DNMT during active GO and is inducible by PDGF-BB.
  • Inhibition of DNMTs or EZH2 suppressed TSHR mRNA expression.
  • Targeting DNMT/EZH2 pathways presents a potential therapeutic strategy for managing GO progression.

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