LINE1 CpG-DNA Hypomethylation in Granulosa Cells and Blood Leukocytes Is Associated With PCOS and Related Traits

Sagvekar, Pooja; Mangoli, Vijay; Desai, Shashvat; Patil, Anushree; Mukherjee, Srabani

doi:10.1210/jc.2016-2645

Cited by 26 publications

(18 citation statements)

References 38 publications

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“…These elements have a high prognostic value in disease prediction and serve as important surrogate indicators of altered global methylation in disease states. Our studies show no change in total genomic 5mC or L1 5'-UTR methylation levels in PBLs or CGCs of women with PCOS compared to healthy controls; though a single CpG site (CpG -4) out of 22 CpG sites that were analyzed was found to be consistently hypomethylated and strongly associated with PCOS susceptibility and its traits of systemic and ovarian androgen-excess (155). We also noted that CGCs exhibited a hypomethylated status relative to PBLs (global as well as CpG-site specific hypomethylation), perhaps to facilitate the expression of ovary-specific genes that are otherwise not functional in PBLs.…”

Section: Epigenetic Studies Conducted In Women With Pcoscontrasting

confidence: 56%

Pathomechanisms of polycystic ovary syndrome Multidimensional approaches

2018

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Polycystic ovary syndrome is a complex endocrine disorder affecting numerous women of reproductive age across the globe. Characterized mainly by irregular menses, hirsutism, skewed LH: FSH ratios and bulky polycystic ovaries, this multifactorial endocrinopathy results in unfavorable reproductive and metabolic sequelae, including anovulatory infertility, type 2 diabetes, metabolic syndrome and cardiovascular disease in later years. Increasing evidence has shown that the manifestation of polycystic ovary syndrome (PCOS) is attributable to a cumulative impact of altered genetic, epigenetic and protein profiles which bring about a systemic dysfunction. While genetic approaches help ascertain role of causal variants in its etiology, tissue-specific epigenetic patterns help in deciphering the auxiliary role of environmental, nutritional and behavioral factors. Proteomics is advantageous, linking both genotype and phenotype and contributing to biomarker discovery. Investigating molecular mechanism underlying PCOS is imperative in order to gain insight into the pathophysiology of PCOS and formulate novel diagnostic and treatment strategies. In this review we have summarized these three aspects, which have been successfully utilized to delineate the pathomechanisms of PCOS.

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Section: Epigenetic Studies Conducted In Women With Pcoscontrasting

confidence: 56%

Pathomechanisms of polycystic ovary syndrome Multidimensional approaches

2018

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“…These findings raised the question of whether changes in DNA methylation were specific to the genomic region and tissue in women with PCOS; however, technical limitations, such as small sample size, could not be eliminated to elucidate these results. Conversely, a decline in the DNA methylation levels of a CpG located at the 5′-untranslated region of long interspersed nucleotide element-1 (L-1) correlated with a global hypomethylated state of the genome in the peripheral blood of women with PCOS compared with controls, as L-1 is a well-known marker for global DNA methylation (Sagvekar et al 2017).…”

Section: Dna Methylation In the Peripheral And Cord Blood From Women mentioning

confidence: 99%

“…Most studies focusing on DNA methylation and PCOS have been conducted in granulosa cells, which play a fundamental role in steroidogenesis and ovarian folliculogenesis and whose dysfunction correlates with the pathogenesis of the disease (Pellatt et al 2007;Lan et al 2015). Some studies have reported differences in the global content of DNA methylation in granulosa cells of women with PCOS compared with controls (Pruksananonda et al 2016, Xu et al 2016, Sagvekar et al 2017, Pan et al 2018. In particular, a global hypomethylated state of the genome in granulosa cells of women with PCOS (evidenced by a decline in the DNA methylation levels of L-1) correlated with the hormonal alterations of the disease (Sagvekar et al 2017).…”

Section: Dna Methylation In the Ovarian Tissue And Granulosa Cells Frmentioning

confidence: 99%

“…Some studies have reported differences in the global content of DNA methylation in granulosa cells of women with PCOS compared with controls (Pruksananonda et al 2016, Xu et al 2016, Sagvekar et al 2017, Pan et al 2018. In particular, a global hypomethylated state of the genome in granulosa cells of women with PCOS (evidenced by a decline in the DNA methylation levels of L-1) correlated with the hormonal alterations of the disease (Sagvekar et al 2017). A genome-wide study revealed that granulosa cells of PCOS women with obesity exhibit variations in the content of DNA methylation compared with PCOS women without obesity (5202 differentially methylated CpGs) and women without the disease (6936 differentially methylated CpGs), albeit the highest difference was observed between PCOS women without obesity and controls (12,245 differentially methylated CpGs), indicating that obesity affects not only the phenotype of women with PCOS but also their epigenetic program (Xu et al 2016).…”

Section: Dna Methylation In the Ovarian Tissue And Granulosa Cells Frmentioning

confidence: 99%

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DNA methylation in the pathogenesis of polycystic ovary syndrome

et al. 2019

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Polycystic ovary syndrome (PCOS) is the leading endocrine and metabolic disorder in premenopausal women characterized by hyperandrogenism and abnormal development of ovarian follicles. To date, the PCOS etiology remains unclear and has been related to insulin resistance, obesity, type 2 diabetes mellitus, cardiovascular disease and infertility, among other morbidities. Substantial evidence illustrates the impact of genetic, intrauterine and environmental factors on the PCOS etiology. Lately, epigenetic factors have garnered considerable attention in the pathogenesis of PCOS considering that changes in the content of DNA methylation, histone acetylation and noncoding RNAs have been reported in various tissues of women with this disease. DNA methylation is changed in the peripheral and umbilical cord blood, as well as in ovarian and adipose tissue of women with PCOS, suggesting the involvement of this epigenetic modification in the pathogenesis of the disease. Perhaps, these defects in DNA methylation promote the deregulation of genes involved in inflammation, hormone synthesis and signaling and glucose and lipid metabolism. Research on the role of DNA methylation in the pathogenesis of PCOS is just beginning, and several issues await investigation. This review aims to provide an overview of current research focused on DNA methylation and PCOS, as well as discuss the perspectives regarding this topic.

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“…Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine metabolic disorders affecting about 5-10% women of reproductive age [1,2]. It is generally characterized by hyperandrogenism, polycystic ovary and anovulation, but also associated with metabolic dysfunction, cardiovascular risk, abnormal granulosa cells (GCs) proliferation as well as arrest of follicle growth [3,4]. The clinical symptoms and signs of PCOS vanished or irregular menstruation, difficulty in pregnancy, acne, as well as thick, dark and smooth skin patches [5].…”

Section: Introductionmentioning

confidence: 99%

miR-132 is up-regulated in polycystic ovarian syndrome and inhibits granulosa cells proliferation via targeting Foxa1

Cui

Xuan

Liu

et al. 2020

Preprint

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Background: Polycystic ovary syndrome (PCOS) is one of the most common endocrine metabolic disorders characterized by hyperandrogenism, polycystic ovaries and ovulatory dysfunction. Several studies have suggested that the aberrant expression of miRNAs serves an important role in the pathogenesis of PCOS, though the role and underling mechanism of microRNA-132 (miR-132) in the development of PCOS remain unclear. Methods: The expression of miR-132 in granulosa cells (GCs) derived from 26 PCOS patients and 30 healthy controls was detected through RT-qPCR. And the apoptosis levels of granulosa cells were measured by TUNEL.Granulosa-like tumor cell line (KGN) was cultured for cell counting kit-8 (CCK-8) was assays after over-expression of miR-132 or knockdown TargetScan was applied to analysis the potential targets of miR-132, which was further verified by luciferase assay, RT-qPCR and western blot. Results: The expression of miR-132 was declined in granulosa cells of PCOS patients. Meanwhile, the significantly increased apoptotic nuclei were present GCs of PCOS patients. Furthermore, over-expressed of miR-132 inhibited the proliferation of KCN cells. In addition, our results verified that miR-132 directly targeted Foxa1, knockdown of which suppressed KGN cells proliferation. Conclusion: Our results revealed that miR-132 inhibits the cell viability and induces apoptosis by directly interacting with Foxa1, indicating a role of miR-132 to be a potential target in the PCOS patients.

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LINE1 CpG-DNA Hypomethylation in Granulosa Cells and Blood Leukocytes Is Associated With PCOS and Related Traits

Abstract: Our study revealed strong association of single hypomethylated CpG-site with PCOS. Identification and characterization of more such methyl-CpG signatures in repetitive elements in larger study populations would provide valuable epigenetic insights into PCOS.

Cited by 26 publications

References 38 publications

Pathomechanisms of polycystic ovary syndrome Multidimensional approaches

Pathomechanisms of polycystic ovary syndrome Multidimensional approaches

DNA methylation in the pathogenesis of polycystic ovary syndrome

miR-132 is up-regulated in polycystic ovarian syndrome and inhibits granulosa cells proliferation via targeting Foxa1

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