Credit: Susanne Harris/Macmillan Publishers Limited

Methyl-CpG-binding protein 2 (MeCP2) is dysregulated in fibroblasts from patients with systemic sclerosis (SSc) and might have a protective role against fibrosis, according to results from a new study. MeCP2 is an epigenetic regulator that binds to methylated DNA.

SSc is a rare disease characterized by autoimmune damage, vascular dysfunction and fibrosis. “We have been using epigenetic characterization on disease-relevant cell types to try to better understand SSc so that better treatment options can be developed,” explains corresponding author Amr Sawalha. “We focused this study on MeCP2 as our group was the first to describe a genetic association between genetic variants in MeCP2 and autoimmunity over a decade ago.”

The researchers found increased expression of MeCP2 in fibroblasts from patients with diffuse cutaneous SSc (dcSSc) compared with fibroblasts from healthy individuals.

Next, the researchers overexpressed MeCP2 in normal dermal fibroblasts. Interestingly, this overexpression of MeCP2 suppressed myofibroblast differentiation and fibroblast proliferation and migration.

RNA sequencing was subsequently used to identify downstream target genes regulated by MeCP2 in dcSSc fibroblasts with and without MeCP2 knockout. Three of the genes identified were PLAU, NID2 and ADA. Functional studies demonstrated that the products of these genes mediated the antifibrotic effects of MeCP2. “We showed that manipulating these genes can mitigate several of the pathologic features in SSc fibroblasts,” says Sawalha.

…increased MeCP2 expression in dcSSc fibroblasts might be a defence mechanism…

The authors suggest that increased MeCP2 expression in dcSSc fibroblasts might be a defence mechanism against fibrosis. “Manipulating MeCP2 or molecules encoded by the MeCP2-target genes we identified could be of therapeutic potential in this debilitating disease,” concludes Sawalha. Future studies of lung fibroblasts or other cell types involved in SSc might also be warranted.