Investigative ophthalmology & visual science · 2026
Epigenetic Modulation of Thyroid-Stimulating Hormone Receptor Expression in Orbital Fibroblasts From Graves' Ophthalmopathy: Target for Treatment.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Chompoowong Rajit, Phankeaw Pimchanok, Suwannavong Apinya, Visamol Sopita, Pitikiadtikun Sukonlaphat, Saonanon Preamjit, Pruksakorn Vannakorn, Potita Panida, Palaga Tanapat, Virakul Sita
Аннотация
PURPOSE: This study aims to investigate the expression and function of DNA methyltransferases (DNMTs) and histone methyltransferase EZH2 in regulating the expression of thyroid-stimulating hormone receptor (TSHR) and fibrotic markers by orbital fibroblasts from Graves' ophthalmopathy (GO) patients.
METHODS: DNMTs mRNA levels were measured in orbital fibroblasts from healthy controls (control orbital fibroblasts), active GO fibroblasts, and inactive GO fibroblasts (iGOFs). TSHR and other fibrotic markers were measured in iGOFs treated with platelet-derived growth factor (PDGF)-BB and decitabine (a DNMT inhibitor) or DZNep (an EZH2 inhibitor) or small interfering RNA by RT-qPCR or Western blotting.
RESULTS: DNMT1 and DNMT3A mRNA expressions were significantly higher in active GOFs compared with iGOFs and control orbital fibroblasts. Among all DNMTs, DNMT1 expression was at the highest levels. Upon PDGF-BB stimulation, DNMT1 and DNMT3A mRNA levels in iGOFs were significantly induced. Decitabine significantly inhibited PDGF-BB-induced cell viability and TSHR mRNA levels in iGOFs, whereas DNMT1 silencing partly reduced TSHR protein. Because a positive correlation between DNMT1 and EZH2 expression in iGOF was observed, the regulatory role of EZH2 on TSHR expression was also investigated. DZNep slightly decreased TSHR mRNA expression in iGOFs and iGO orbital tissue, whereas EZH2 silencing partly affects TSHR expression.
CONCLUSIONS: This study demonstrates that DNMT1 is the major DNMT during the active stage of GO. Moreover, DNMT1 is inducible upon PDGF-BB stimulation in iGOFs, suggesting an important role of PDGF-BB and DNMT1 during an active stage of GO. Our findings also highlighted that the inhibition of DNMT or EZH2 potentially suppressed TSHR mRNA expression, suggesting potential therapies targeting DNMT/EZH2 in controlling GO progression.
METHODS: DNMTs mRNA levels were measured in orbital fibroblasts from healthy controls (control orbital fibroblasts), active GO fibroblasts, and inactive GO fibroblasts (iGOFs). TSHR and other fibrotic markers were measured in iGOFs treated with platelet-derived growth factor (PDGF)-BB and decitabine (a DNMT inhibitor) or DZNep (an EZH2 inhibitor) or small interfering RNA by RT-qPCR or Western blotting.
RESULTS: DNMT1 and DNMT3A mRNA expressions were significantly higher in active GOFs compared with iGOFs and control orbital fibroblasts. Among all DNMTs, DNMT1 expression was at the highest levels. Upon PDGF-BB stimulation, DNMT1 and DNMT3A mRNA levels in iGOFs were significantly induced. Decitabine significantly inhibited PDGF-BB-induced cell viability and TSHR mRNA levels in iGOFs, whereas DNMT1 silencing partly reduced TSHR protein. Because a positive correlation between DNMT1 and EZH2 expression in iGOF was observed, the regulatory role of EZH2 on TSHR expression was also investigated. DZNep slightly decreased TSHR mRNA expression in iGOFs and iGO orbital tissue, whereas EZH2 silencing partly affects TSHR expression.
CONCLUSIONS: This study demonstrates that DNMT1 is the major DNMT during the active stage of GO. Moreover, DNMT1 is inducible upon PDGF-BB stimulation in iGOFs, suggesting an important role of PDGF-BB and DNMT1 during an active stage of GO. Our findings also highlighted that the inhibition of DNMT or EZH2 potentially suppressed TSHR mRNA expression, suggesting potential therapies targeting DNMT/EZH2 in controlling GO progression.
Предметные рубрики MeSH
HumansGraves OphthalmopathyFibroblastsReceptors, ThyrotropinRNA, MessengerCells, CulturedEpigenesis, GeneticBlotting, WesternBecaplerminFemaleGene Expression RegulationProto-Oncogene Proteins c-sisOrbitDNA (Cytosine-5-)-Methyltransferase 1DNA Methyltransferase 3AEnhancer of Zeste Homolog 2 ProteinAdultMaleDNA (Cytosine-5-)-MethyltransferasesDecitabineMiddle AgedAzacitidine