Fig. 2

Schematic representation of key epigenetic mechanisms (DNA methylation, histone modification, and miRNA) involved in the pathogenesis of Familial Mediterranean Fever (FMF). (A) DNA methylation of the CpG island covering the entire exon 2 of MEFV gene leads to a decrease in the gene expression and to exon 2 skipping, hence resulting in an increase in spliced transcripts of exon 2 (MEFV-d2) and an abnormal localization of d-2 pyrin protein in the nucleus. Such changes may contribute to FMF pathogenesis and phenotypic variability among patients. (B) Acetylation of H3K9 and H4 histones of the NLRP3 gene promoter results in an increase of NLRP3 gene expression and inflammasome activation. The role of histone modifications in FMF pathogenesis has not yet been elucidated. (C) miRNAs, such as mir-204-3p, mir-197-3p, mir-4520a, mir-16-5p, mir-195-5p, mir-17-5p, mir-25, and mir-181b-5p, present variable expression in FMF patients. These miRNAs are involved through various signaling pathways in many processes such as inflammation, autophagy, and apoptosis. For example, the downregulation of mir-204-3p in FMF was found to activate PI3K leading to the phosphorylation of Akt which in turn activates NF-κB that promotes the expression of pro-inflammatory cytokines such as IL-6 and IL-12p40, triggering inflammation. Similarly, the downregulation of mir-197-3p in FMF leads to inflammation by increasing the expression of IL-1R1, activating downstream NF-κB which promotes the expression and release of IL-1β. Moreover, the upregulation of mir-4520a in FMF patients was found to further inhibit RHEB, inactivating the mTORC1 pathway and promoting the phosphorylation of ULK1 which induces autophagy. Overexpression of both mir-16-5p and mir-195-5p in FMF patients leads to the activation of caspase-9 and caspase-3, inducing apoptosis. As for mir-17-5p, its down-expression in FMF was found to increase the expression of PTEN which inhibits the conversion of PIP2 to PIP3, preventing the phosphorylation of Akt, and inducing apoptosis. Finally, the upregulation of mir-181b-5 activates MEK and ERK, hence increasing the expression of p21 and repressing apoptosis. Act: Acetylation; Akt: Protein kinase B; DNMT: DNA methyltransferases; ERK: Extracellular signal-regulated kinase; IL: Interleukin; IL1-R1: Interleukin-1-receptor-1; LPS: Lipopolysaccharide; MEFV: MEditerranean FeVer; MEK: Mitogen-activated protein kinase; Met: Methylation; mTOR: Mammalian target of rapamycin; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; P: Phosphorylation; PIP2: Phosphatidylinositol 4,5-bisphosphate; PIP3: Phosphatidylinositol 3,4,5-triphosphate; PI3K- γ: Phosphoinositide 3-kinases gamma; PTEN: Phosphatase and tensin homolog; RAF: Rapidly accelerated fibrosarcoma; RAS: Rat sarcoma; RHEB: Ras homolog enriched in brain; SAM: S-Adenosylmethionine; SUMO: SUMOylation; TLR4: Toll-like receptor 4; Ub: Ubiquitylation; ULK1: Unc-51 like autophagy activating kinase 1