Fig. 2

HFD-induced hypermethylation in three CpG sites of RNF43 that negatively regulate Wnt signaling. (A) Gene map of RNF43 and Wnt recognition elements (WREs). WRE1 (red triangles) and WRE2 (black triangles) are indicated. Other symbols mirror those in Fig. 1. (B) Averaged β-values of three CpGs in RNF43 in HFD-and NFD-mouse pancreatic cells. Methylation levels in three CpGs (#13, #15 and #25) increased in HFD-fed mice (n = 7), compared with those in NFD-fed mice (n = 5) (*,P < 0.05; two-sided Student’s t-test). (C) Schematic representation of the signal transduction pathway activated by obesity in mouse pancreas. Wnt proteins bind to its cognate receptor, Frizzeled (FZD), and translocate β-catenin/TCF complex into nuclei, leading to target gene expression through binding to its translational element (WRE). RNF43 ubiquitinates FZD and induces endocytosis, downregulating the Wnt signaling.