X chromosome gene methylation in peripheral lymphocytes from monozygotic twins discordant for scleroderma

Abstract

SummaryScleroderma (SSc) is a rare connective tissue disease characterized by fibrosis, microvasculopathy and autoimmune features. The role of genetics is limited in SSc, as suggested by similar concordance rates in monozygotic and dizygotic twin pairs, while environmental factors may act through epigenetic changes, as demonstrated for specific genes. Further, sex chromosome changes have been reported in SSc and may explain the female preponderance. In the present study we compared the methylation profile of all X chromosome genes in peripheral blood mononuclear cells from monozygotic twins discordant (n = 7) and concordant (n = 1) for SSc. Methylated DNA immunoprecipitations from each discordant twin pair were hybridized to a custom-designed array included 998 sites encompassing promoters of all X chromosome genes and randomly chosen autosomal genes. Biostatistical tools identified sites with an elevated probability to be consistently hypermethylated (n = 18) or hypomethylated (n = 25) in affected twins. Identified genes include transcription factors (ARX, HSFX1, ZBED1, ZNF41) and surface antigens (IL1RAPL2, PGRMC1), and pathway analysis suggests their involvement in cell proliferation (PGK1, SMS, UTP14A, SSR4), apoptosis (MTM1), inflammation (ARAF) and oxidative stress (ENOX2). In conclusion, we propose that X chromosome genes with different methylation profiles in monozygotic twin pairs may constitute candidates for SSc susceptibility.

The role of genetics and epigenetics in the pathogenesis of systemic sclerosis

“…56 Supporting this hypothesis, the DNA methylation profile of peripheral blood mono nuclear cells from monozygotic twins discordant for SSc showed that only X chromosome sites were consistently either hypermethylated or hypomethylated. 57 However, these observations fail to demonstrate the functional consequence of the altered DNA methylation pattern on the phenotype of peripheral leukocytes from patients with SSc. Another report indicated that increased DNA methylation of regulatory sequences in FOXP3 from CD4 + T cells from patients with SSc affected the expres sion of this key transcription factor, which is required for the generation of regulatory T cells.…”

Disease Manifestation and Inflammatory Activity as Modulators of Th17/Treg Balance and RORC/FoxP3 Methylation in Systemic Sclerosis

“…RORγ and RORγτ are gene products of RORC1 and RORC2 genes, respectively, with RORγτ being strongly involved in polarization of Th cells towards Th17. Epigenetic regulation of T-cell-specific transcription factors by methylation of regulatory CpG sites has been suggested to influence the pathogenesis of SSc [21,22,23,24,25]. …”

Lessons learned from twins in autoimmune and chronic inflammatory diseases

“…We are convinced that environmental factors are central to SSc pathogenesis and may act through epigenetic changes, particularly DNA methylation [52]. Our group has previously demonstrated that the methylation profile of the X chromosome in MZ discordant and concordant SSc twins varies according to disease status, thus suggesting that different methylation profiles in MZ twin pairs may constitute candidates for SSc susceptibility [53]. In SSc, hypermethylated CpG islands are found in the Fli1 promoter, which is a transcription factor that inhibits collagen production.…”