Methyl cap binding protein 2: A key epigenetic protein in systemic sclerosis

John Henderson, Max Brown, Steven Horsburgh, Laura Duffy, Sarah Wilkinson, Julie Worrell, Richard Stratton, Steven O'Reilly*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Objective SSc is an autoimmune connective tissue disease that results in skin fibrosis and currently has no effective treatment. Epigenetic modifications have been described and these may be key in initiating and driving fibroblast activation. Among these epigenetic modifications methylation may be of central importance. The aim of this study was to examine the role of methyl cap binding protein-2 (MeCP2) in SSc fibrosis. Methods We used healthy and SSc dermal fibroblasts to examine the role of MeCP2, using both small interfering RNA silencing and lentiviral overexpression to determine its effects. We also examined the expression of MeCP2 in SSc fibroblasts by immunoblotting. miRNA132 was quantified by Taqman real time PCR. Results We demonstrated that TGF-β1 induced the expression of MeCP2 in normal cells, and showed that SSc fibroblasts expressed high levels of MeCP2 under basal conditions. MeCP2 positively regulated the expression of extracellular matrix through epigenetic repression of the Wnt antagonist sFRP-1, leading to enhanced Wnt signalling. This mediated fibrosis through glycolysis, as the glycolysis inhibitor 2-deoxyglucose diminished the Wnt-mediated collagen expression. MiR132 expression was reduced in SSc fibroblasts. Conclusion The results suggest that an epigenetic loop exists mediating fibrosis. Targeting of MeCP2, as a key epigenetic regulator, may be a promising therapeutic approach, as would targeting the metabolic reprogramming that occurs through aerobic glycolysis.

Original languageEnglish
Pages (from-to)527-535
Number of pages9
JournalRheumatology (United Kingdom)
Volume58
Issue number3
Early online date20 Nov 2018
DOIs
Publication statusPublished - 1 Mar 2019

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