Amandine Charras

An in silico Approach Reveals Associations between Genetic and Epigenetic Factors within Regulatory Elements in B Cells from Primary Sjögren's Syndrome Patients.

Recent advances in genetics have highlighted several regions and candidate genes associated with primary Sjögren’s syndrome (SS), a systemic autoimmune epithelitis that combines exocrine gland dysfunctions, and focal lymphocytic infiltrations. In addition to genetic factors, it is now clear that epigenetic deregulations are present during SS and restricted to specific cell type subsets, such as lymphocytes and salivary gland epithelial cells. In this study, 72 single nucleotide polymorphisms (SNPs) associated with 43 SS gene risk factors were selected from publicly available and peer reviewed literature for further in silico analysis. SS risk variant location was tested revealing a broad distribution in coding sequences (5.6%), intronic sequences (55.6%), upstream/downstream genic regions (30.5%), and intergenic regions (8.3%). Moreover, a significant enrichment of regulatory motifs (promoter, enhancer, insulator, DNAse peak, and expression quantitative trait loci) characterizes SS risk variants (94.4%). Next, screening SNPs in high linkage disequilibrium (r2 ≥ 0.8 in Caucasians) revealed 645 new variants including 5 SNPs with missense mutations, and indicated an enrichment of transcriptionally active motifs according to the cell type (B cells > monocytes > T cells ≫ A549). Finally, we looked at SS risk variants for histone markers in B cells (GM12878), monocytes (CD14+) and epithelial cells (A548). Active histone markers were associated with SS risk variants at both promoters and enhancers in B cells, and within enhancers in monocytes. In conclusion and based on the obtained in silico results that need further confirmation, associations were observed between SS genetic risk factors and epigenetic factors and these associations predominate in B cells, such as those observed at the FAM167A–BLK locus.

Primary Sjögren’s Syndrome and Epigenetics

Abstract Primary Sjogrens syndrome (pSS) is a systemic autoimmune epithelitis characterized by exocrine gland dysfunction (with lymphocytic infiltrations predominantly in the salivary and lacrimal glands) and B-cell hyperactivation. The etiology of pSS is multifactorial, and there is increasing evidence to suggest that epigenetic factors may also be determinant in the physiopathology of pSS. Epigenetics is defined as stable heritable changes in gene expression not attributable to genomic DNA. Peripheral blood T cells, peripheral B cells, and minor salivary gland (MSG) tissue from pSS patients show abnormal DNA methylation. This process has been characterized and the consequences for MSGs include: (1) the overexpression of transposons; (2) an epigenetic change in genes controlling autoantigens, antigen presentation, interferon signaling, and calcium signaling; (3) defective control of microRNAs; and (4) altered chromatin positioning associated with autoantibody production. Cell-specific cross talk between epigenetic and genetic factors is also suspected to promote autoreactivity. Epigenetic modifications in MSG are reversible as observed following B-cell depletion. Thus the epigenetic findings in pSS will provide new perspectives for therapeutic approaches, as well as the possibility to identify new biomarkers.