Sex-specific epigenetics drive low GPER expression in gastrointestinal smooth muscles in Type 2 diabetic mice
Type 2 diabetes mellitus (T2DM) causes gastroparesis, delayed intestinal transit, and constipation, for unknown reasons. Complications are predominant in men and postmenopausal women, suggesting a female hormone-mediated mechanism. Low G-protein coupled estrogen receptor (GPER) expression from epigenetic modifications may explain it. We explored sexually differentiated GPER expression and gastrointestinal symptoms related to GPER alterations in wild-type (WT) and T2DM mice (db/db). GPER mRNA and protein expression, DNA methylation and histone modifications were measured from stomach and colon samples of db/db and WT mice. We found that WT female tissues have the highest GPER mRNA and protein expressions. The expression is lowest in all db/db. The lowest mRNA levels are in the male stomach and female colon. GPER downregulation is associated with promoter hypermethylation and reduced enrichment of H3K4me3 and H3K27ac marks around the GPER promoter. T2DM impairs gut GPER expression, and epigenetic sex-specific mechanisms matter in the downregulation. Overall design: To investigate the GPER expression in male and female gastric and colonic smooth muscle of wild-type and db/db (type 2 diabetic) mice, we performed DNA-methylation measurement at the GPER promoter region by targeted bisulfite sequencing assay. This was performed in the colonic and gastric tissue of 5 male wild-type, 5 male db/db, 4 female wild-type, and 6 db/db female mice. The DNA methylation data was analyzed by comparative analysis, using ANOVA.