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Gene regulatory activity associated with PCOS reveals DENND1A-dependent testosterone production

ABSTRACT: Polycystic Ovary Syndrome (PCOS) is a leading cause of infertility. About 5 million women in the US have PCOS, making it the most prevalent endocrine disorder among menstruating people. Despite that prevalence, the underlying causes remain unknown. Genome-wide association studies (GWAS) have identified non-coding genetic variation associated with PCOS risk and identifying the underlying molecular mechanisms is currently a major opportunity for improving diagnosis and treatment. We report the discovery of gene regulatory mechanisms that help explain genetic association with PCOS in the GATA4, FSHB and DENND1A loci. We based those findings using a combination of high throughput reporter assays, CRISPR-based epigenome editing, and genetic association analysis from PCOS case and control populations. In addition, we found that elevated endogenous DENND1A expression causes elevated testosterone levels, a hallmark PCOS phenotype. These results further highlight the potential for combining genetic variant analyses with experimental approaches to fine map genetic associations with disease risk.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262471 | GEO | 2024/03/30

REPOSITORIES: GEO

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Project description:Insulin resistance is a common metabolic abnormality in women with PCOS and leads to an elevated risk of type 2 diabetes. Studies have shown that thiazolidinediones (TZD) improve metabolic disturbances in PCOS patients. We hypothesized that the effect of TZD in PCOS is in part mediated by changes in the transcriptional profile of muscle favoring insulin sensitivity. Using Affymetrix microarrays, we examined the effect of pioglitazone (30 mg/day for 16 weeks) on gene expression in skeletal muscle of 10 obese women with PCOS metabolically characterized by a euglycemic-hyperinsulinemic clamp. Moreover, we explored gene expression changes between these PCOS patients before treatment and 13 healthy control women. Treatment with pioglitazone improved insulin-stimulated total, oxidative and non-oxidative glucose metabolism, and reduced fasting serum insulin (all p < 0.05). Global pathway analysis using Gene Map Annotator and Pathway Profiler (GenMAPP 2.1) and Gene Set Enrichment Analysis (GSEA 2.0.1) revealed a significant upregulation of genes involved in mitochondrial oxidative phosphorylation (OXPHOS), ribosomal proteins, mRNA processing reactome, translation factors, and proteasome complexes in PCOS patients after pioglitazone therapy. Quantitative real-time PCR suggested that upregulation of OXPHOS genes was mediated by an increase in PGC-1M-NM-1 expression (p < 0.05). Expression of genes involved in ribosomal proteins and OXPHOS was down-regulated in PCOS patients before treatment compared to matched healthy women using GenMAPP 2.1 and GSEA 2.1. These data indicate that pioglitazone therapy restores insulin sensitivity in part by a coordinated upregulation of genes involved in mitochondrial oxidative metabolism and protein biosynthesis in skeletal muscle of PCOS. These transcriptional effects of pioglitazone therapy may contribute to prevent the onset of type 2 diabetes in these women. Experiment Overall Design: Ten obese women of reproductive age with PCOS participated in the study to test the effect of pioglitazone therapy (data set 1). To test if pioglitazone ameliorate existing defects in PCOS patients, the expression profile of the 10 PCOS patients before treatment were compared to the same cohort of 13 control subjects (data set 2).

Project description:Insulin resistance is a common metabolic abnormality in women with PCOS and leads to an elevated risk of type 2 diabetes. Studies have shown that thiazolidinediones (TZD) improve metabolic disturbances in PCOS patients. We hypothesized that the effect of TZD in PCOS is in part mediated by changes in the transcriptional profile of muscle favoring insulin sensitivity. Using Affymetrix microarrays, we examined the effect of pioglitazone (30 mg/day for 16 weeks) on gene expression in skeletal muscle of 10 obese women with PCOS metabolically characterized by a euglycemic-hyperinsulinemic clamp. Moreover, we explored gene expression changes between these PCOS patients before treatment and 13 healthy control women. Treatment with pioglitazone improved insulin-stimulated total, oxidative and non-oxidative glucose metabolism, and reduced fasting serum insulin (all p < 0.05). Global pathway analysis using Gene Map Annotator and Pathway Profiler (GenMAPP 2.1) and Gene Set Enrichment Analysis (GSEA 2.0.1) revealed a significant upregulation of genes involved in mitochondrial oxidative phosphorylation (OXPHOS), ribosomal proteins, mRNA processing reactome, translation factors, and proteasome complexes in PCOS patients after pioglitazone therapy. Quantitative real-time PCR suggested that upregulation of OXPHOS genes was mediated by an increase in PGC-1α expression (p < 0.05). Expression of genes involved in ribosomal proteins and OXPHOS was down-regulated in PCOS patients before treatment compared to matched healthy women using GenMAPP 2.1 and GSEA 2.1. These data indicate that pioglitazone therapy restores insulin sensitivity in part by a coordinated upregulation of genes involved in mitochondrial oxidative metabolism and protein biosynthesis in skeletal muscle of PCOS. These transcriptional effects of pioglitazone therapy may contribute to prevent the onset of type 2 diabetes in these women. Keywords: PCOS, microarray, global pathway analysis, insulin resistance, pioglitazone, protein metabolism, mitochondrial oxidative metabolism

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Gene regulatory activity associated with PCOS reveals DENND1A-dependent testosterone production

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