Epigenetic Changes May Be Involved in Scleroderma Development, Study Says

Epigenetic changes — chemical modifications in DNA that affect gene expression (the process by which information within a gene gives rise to a functional product) — may be involved in the development of systemic scleroderma, a study says.

The findings of the study, “Integrative analysis of DNA methylation in discordant twins unveils distinct architectures of systemic sclerosis subsets,” were published in the journal Clinical Epigenetics.

Scleroderma is a chronic autoimmune disorder that affects the connective tissue — the tissue that holds together other tissues in the body and supports the organs — and is characterized by scarring (fibrosis) of the skin and internal organs. In systemic scleroderma, also known as systemic sclerosis (SSc), the degree of scarring in internal organs is quite profound.

There are two subtypes of SSc, depending on the degree of skin involvement: limited cutaneous SSc (lower skin involvement, lcSSc); or diffuse cutaneous SSc (higher skin involvement, dcSSc).

Up until now, not much has been known about the specific causes of SSc, although scientists believe it may result from a combination of genetic and environmental factors. DNA methylation — one of the most common epigenetic modifications associated with gene inactivation, or silencing — has been suggested to be involved in several autoimmune diseases.

“There is compelling evidence that DNA methylation plays a role in the [development] of autoimmune diseases, and multiple epigenome-wide association studies revealed the existence of differentially methylated regions associated with, for example, systemic lupus erythematosus (SLE), rheumatoid arthritis, or psoriasis,” the investigators wrote.

In the case of SSc, previous studies have also identified genome regions that were differentially methylated in different cell types, raising the possibility that epigenetic modifications may play a role in disease development.

Now, a group of researchers from the Medical University of South Carolina, along with their collaborators, set out to analyze the patterns of DNA methylation in pairs of disease-discordant twins (one sibling had SSc, but the other did not) to minimize confounding effects arising from different genetic backgrounds, age, sex, or early-life environmental factors.

The team analyzed a total of 27 pairs of twins (19 identical and eight non-identical) — 18 in which one of the siblings had lcSSc and nine in which one of the siblings had dcSSc. All participants provided blood samples for genomic methylation analysis.

Results showed that affected siblings had unique differentially methylated sites (153 in those with lcSSc, and 266 in those with dcSSc), suggesting the existence of a specific DNA methylation pattern associated with SSc.

Moreover, comparison analyses showed that 76 of these unique differentially methylated sites had also been found in blood cells from patients with lupus, supporting the hypothesis that these specific epigenetic modifications might be linked to autoimmunity.

In addition, analyses also identified a total of 27 genes containing unique epigenetic modifications whose expression in blood samples from affected siblings was different from healthy siblings (e.g. IFI44L and RSAD2).

Further analyses revealed that in siblings with dcSSc, but not in those with lcSSc, epigenetic modifications were frequently found in gene regulatory regions; that is, specific sites within genes that are responsible for controlling gene expression. Interestingly, some of these modified regulatory regions were found in monocytes and macrophages, which are immune cells involved in fibrosis, indicating that epigenetic modifications might be responsible for immune cells’ dysregulation in dcSSc.

Overall, “although this cross-sectional study cannot separate causality from response to disease, it identifies epigenetically modified genes and pathways that are important in SSc,” the researchers said.

In particular, the “results show that DNA methylation sites in dcSSc patients are enriched for regulatory regions in cell types with key roles in fibrosis, implicating DNA methylation as a modulator of cell functionality. Coupled with the observation that dcSSc and lcSSc are epigenetically distinct disease subtypes, this suggests that the cellular dysfunction observed in dcSSc is, at least partially, due to an epigenetic disregulation of myeloid cell types,” they stated.

The team also emphasized that further research is needed “to determine if the differentially methylated functional [regions] represent attractive targets for the treatment or prevention of autoimmune- and/or fibrotic-related diseases.”