The Epigenetic Signature of Systemic Sclerosis with a Focus on Endothelial-to-Mesenchymal and Epithelial-to-Mesenchymal Transitions

Systemic sclerosis (SSc) is an immune-mediated connective tissue disease (CTD) with a unique pathogenetic profile. Along with the abnormal activation of the immune response, a feature shared with other CTDs, the pathogenesis of SSc also involves two key processes: microangiopathy and fibrosis. The underlying mechanisms are still under active investigation. In genetically predisposed individuals, environmental triggers such as infections or exposure to certain chemicals and toxins may cause endothelial damage, leading to the transdifferentiation of endothelial cells into myofibroblasts. These cells are the primary contributors to both microvascular alterations and connective tissue fibrosis. Myofibroblasts express typical mesenchymal cell markers, including α-smooth muscle actin (α-SMA), and produce extracellular matrix (ECM), which can result in organ failure. The transition to a mesenchymal phenotype is a gradual process known as endothelial-to-mesenchymal transition (Endo-MT). A similar process can also occur in epithelial cells, where it is called epithelial-to-mesenchymal transition (EMT). Physiologically, Endo-MT and EMT play roles in organogenesis and wound repair. However, the occurrence of Endo-MT and EMT in adults has been linked to several pathological conditions, with SSc being a prominent example. Both Endo- MT and EMT may result from significant epigenetic changes, during which genes crucial to vasculopathy or fibrosis are reversibly switched on or off. In this chapter, we review evidence for epigenetic signatures – such as DNA methylation patterns, histone modifications, and aberrant expression of noncoding RNAs (ncRNAs) – that may regulate Endo-MT and EMT in SSc or preclinical models of the disease.