Dataset Information

Sex-specific epigenetics drive low GPER expression in gastrointestinal smooth muscles in Type 2 diabetic mice

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE240515 | GEO | 2023/12/15

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Introduction: Type 1 diabetes (T1D) significantly affects gastrointestinal (GI) motility and contributes to complications, such as gastroparesis, constipation, and fecal incontinence. Notably, these complications have a higher prevalence in female patients, underscoring a critical knowledge gap in the understanding of the underlying mechanisms. Given the emerging role of the G-protein-coupled estrogen receptor (GPER) in GI motility regulation, our study investigated the potential contribution of diabetes-induced changes in GPER expression to pathophysiology. Hypothesis: We hypothesized that diabetes-induced perturbations in GPER expression contribute to pathophysiological mechanisms affecting GI motility in T1D, with notable sex-dependent variations. Methods: we assessed GPER mRNA and protein expression levels using quantitative reverse-transcription PCR and western blot analyses, and quantified the changes in nuclear DNA methyltransferases and histone modifications (H3K4Me3, H3Ac, and H3K27Ac) were quantified using ELISA kits. Targeted bisulfite and chromatin immunoprecipitation sequencing were used to evaluate DNA methylation and histone modifications around the GPER promoter by chromatin immunoprecipitation assays in gastric and colonic smooth muscle tissues of male and female control (CTR) and non-obese diabetic (NOD) mice. Results: Our results revealed significant downregulation of GPER in NOD mice, with marked sex-dependent variations. Mechanistically, this downregulation was associated with reduced H3K4me3, H3ac, and H3K27ac levels in NOD male gastric smooth muscle. In contrast, downregulation in female gastric smooth muscle cells has been linked to decreased H3K4me3 and H3ac levels. Male NOD colonic smooth muscle exhibited elevated H3ac and H3K27ac levels, whereas female NOD colonic smooth muscle demonstrated diminished enrichment of H3ac and H3K27ac at the GPER promoter. Additionally, DNA methylation is elevated in NOD male colonic smooth muscle compared to NOD females. Conclusion: Our findings elucidate sex-specific epigenetic mechanisms contributing to T1D-mediated suppression of GPER expression in the gastrointestinal tract. These insights not only advance our understanding of T1D complications but also suggest promising avenues for targeted therapeutic interventions.

Project description:STIM1 is an endoplasmic reticulum (ER) calcium (Ca2+) sensor that serves to replenish ER Ca2+ stores in response to ER Ca2+ depletion through gating of plasmalemmal Orai1 channels in a process known as store operated calcium entry (SOCE). Previously, we have shown that SOCE is impaired in the diabetic pancreatic β cell; however, the consequences of reduced β cell SOCE have not been well studied. To test this, we generated mice with pancreatic β cell specific deletion of STIM1 (STIM1Δβ). Our results revealed a striking sexual dimorphism in metabolic phenotypes when STIM1Δβ mice were challenged with high fat diet for 8 weeks. Male STIM1Δβ mice showed no differences in total weight, lean or fat mass, or glucose tolerance compared to WT littermate controls. In contrast, female STIM1Δβ mice displayed significantly increased total body weight, fat mass, and reduced glucose tolerance, in vivo glucose-stimulated insulin secretion and β cell mass compared to WT littermate controls, while insulin sensitivity, food intake, and energy expenditure were unchanged. To investigate mechanisms underlying these findings, RNA sequencing was performed in isolated islets and revealed altered 17-beta estradiol (E2) signaling, lipid metabolism, epithelial cell differentiation and decreased noncanonical estradiol receptor GPER. Consistent with this, alpha cell mass was increased in female STIM1Δβ, while proteomics and immunoblot analysis of STIM1 knockout (STIM1KO) INS-1 beta cells revealed reduce insulin expression and increased glucagon expression, suggesting STIM1 may be required for the maintenance of β cell identity. To this end, we show that a reduction of a noncanonical estradiol receptor GPER in STIM1 deficient islets contributes to the marked sexual dimorphism observed during beta cell dysfunction in female STIM1Δβ mice. This present study delineates a sexually dimorphic regulation of STIM1 in the maintenance of pancreatic beta cell identity through GPER and may expand the field of therapeutic approaches to diabetes. Our findings demonstrate the importance of STIM1 and GPER expression stability in the anti-diabetogenic response from estradiol.

Dataset Information

Sex-specific epigenetics drive low GPER expression in gastrointestinal smooth muscles in Type 2 diabetic mice

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets