Characterization of DNA Methylation and Screening of Epigenetic Markers in Polycystic Ovary Syndrome

Cao, Pengbo; Yang, Wanting; Wang, Peijun; Li, Xihe; Nashun, Buhe

doi:10.37247/pabsc.1.2021.32

Cited by 3 publications

(3 citation statements)

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“…accumulating evidence supports the notion that aberrant gene methylation is a key contributing factor in the pathogenesis of PcoS (44,45). Methylation of numerous genes regulating vital ovarian functions has been previously found to be altered according to the DNA methylome profiling data of granulosa cells (46).…”

Section: Discussionmentioning

confidence: 53%

Ferroptosis inhibitor ferrostatin‑1 alleviates homocysteine‑induced ovarian granulosa cell injury by regulating TET activity and DNA methylation

Shi

Chen

2022

Mol Med Rep

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Polycystic ovary syndrome is one of the most common endocrine and metabolic gynecological disorders, of which dysfunction of ovarian granulosa cells is a key contributing factor. The aim of the present study was to explore the role of ferrostatin-1 (Fer-1), a ferroptosis inhibitor, in a cell injury model established by homocysteine (Hcy)-induced ovarian granulosa KGn cell line and the potential underlying mechanism. cell viability was measured using cell counting Kit-8 assay in the presence or absence of Hcy and Fer-1. cell apoptosis was assessed using Tunel staining and the expression levels of apoptosis-related proteins were measured using western blotting. To explore the effects of Fer-1 on oxidative stress in Hcy-treated ovarian granulosa cells, the levels of reactive oxygen species (roS), malondialdehyde (Mda), lactate dehydrogenase (ldH) and glutathione (GSH) were measured using their corresponding kits. Furthermore, Fe 2+ levels were assessed using Phen Green™ SK labeling and western blotting was performed to measure the protein expression levels of ferroptosis-associated proteins GPX4, Slc7a11, aScl4 and dMT1. Subsequently, dna methylation and ten-eleven translocation (TeT) 1/2 demethylase levels were also detected to evaluate the extent of overall dna methylation in ovarian granulosa cells after Hcy treatment. The TeT1/2 inhibitor Bobcat339 hydrochloride was applied to treat ovarian granulosa cells before evaluating the possible effects of Fer-1 on TeT1/2 and dna methylation. Fer-1 was found to markedly elevate ovarian granulosa cell viability following Hcy treatment. The apoptosis rate in Fer-1-treated groups was also markedly decreased, which was accompanied by downregulated Bax and cleaved caspase-3 expression and upregulated Bcl-2 protein expression. in addition, Fer-1 treatment reduced the levels of roS, Mda and ldH whilst enhancing the levels of GSH. Fe 2+ levels were significantly decreased following Fer-1 treatment, which also elevated glutathione peroxidase 4 expression whilst reducing solute carrier family 7 member 11, achaete-scute family BHlH transcription factor 4 and divalent metal transporter 1 protein expression. Fer-1 significantly inhibited dna methylation and enhanced TeT1/2 levels, which were reversed by treatment with Bobcat339 hydrochloride. Subsequent experiments on cell viability, oxidative stress, Fe 2+ content, ferroptosis-and apoptosis-related proteins levels revealed that Bobcat339 hydrochloride reversed the effects of Fer-1 on ovarian granulosa Hcy-induced cell injury. These results suggest that Fer-1 may potentially protect ovarian granulosa cells against Hcy-induced injury by increasing TeT levels and reducing dna methylation.

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Section: Discussionmentioning

confidence: 53%

Ferroptosis inhibitor ferrostatin‑1 alleviates homocysteine‑induced ovarian granulosa cell injury by regulating TET activity and DNA methylation

Shi

Chen

2022

Mol Med Rep

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“…The pathogenesis of PCOS is in uenced by genomic alterations involving modi cation of the epigenome leading to non-DNA encoded protein expression (Cao et al 2021). Since the rst study over a decade ago (Xu et al 2010), several genome-wide sequencing assays have identi ed small non-coding micro-RNA levels, histone acetylation and histone/DNA methylation patterns as critical epigenetic mechanisms in PCOS-associated cardiometabolic and neuropsychological pathologies (Cui et al 2018;Wang et al 2019;Chen et al 2021).…”

Section: Introductionmentioning

confidence: 99%

“…DNA methylation is an enzymatic reaction involving the addition of a methyl group to the DNA promoter region by methyltranseferases causing transcriptional gene repression (Illingworth et al 2008). In PCOS, DNA methylation differentially affects genes that regulate steroid synthesis, in ammation and metabolism, and these patterns have been recorded in various tissues including ovary, adipose tissue, skeletal muscle and hypothalamus (Shorakae et al 2018;Cui et al 2018;Cao et al 2021). Moreso, histone alterations (involving removal or addition of acetyl or methyl functional groups to/from chromatin histone proteins) determines DNA accessibility and gene expression (Tsankova et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Acetate meliorates depressive-like behaviour in a rat model of PCOS through suppression of HDAC2 expression and DNA methylation

Wolugbom

Areloegbe

Olaniyi

2022

Preprint

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ObjectivePolycystic Ovarian Syndrome (PCOS) is the most common endocrine disorder among women of reproductive age. PCOS has been demonstrated to induce depressive-like behaviour. Epigenetic alterations such as histone deacetylation (HDAC) and DNA methylation have been suggested in major depression. However, their effects with respect to neuroinflammation are not clear. This study therefore investigated the pathogenic role of epigenetic modification in PCOS-associated depression and the therapeutic potential of HDACi, acetate.MethodsAdult female Wistar rats (120-150 g) were allotted into groups (n = 6/group) namely: control (vehicle; p.o.), acetate-treated (200 mg/kg), letrozole (LET)-treated (1 mg/kg) and LET+Acetate-treated. Letrozole was administered for 21 days to induce PCOS.ResultsTreatment with letrozole caused hyperandrogenism, hyperinsulinemia and disrupted ovarian morphology with evidence of degenerated follicles. In addition, these animals showed depressive-like behaviours and increased expression of HDAC2 and DNA methyltransferase in PFC and hippocampal tissues. Biochemical analyses showed elevated NF-kB and acetylcholine (ACH) levels in PFC and hippocampus as well as plasma lipid peroxidation and impaired antioxidant system in LET-treated animals. Histological analysis of PFC and hippocampus showed neurodegeneration in LET-treated animals compared with control. However, these alterations were attenuated when treated with acetate.ConclusionThe study demonstrates that PCOS-associated depression is characterised by neuroinflammation and elevated ACH levels, and this is associated with increased expression of HDAC2 and DNA hypermethylation in PFC and hippocampus. Besides, the study suggests that acetate ameliorates PCOS-associated depression through the suppression of prefrontal and hippocampal DNA methyltransferase and prefrontal but not hippocampal HDAC2 expression.

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Understanding polycystic ovary syndrome in light of associated key genes

Bhimwal,

Puneet,

Priyadarshani

2023

Egypt J Med Hum Genet

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Background Polycystic ovary syndrome (PCOS) is an endocrinopathy affecting women of reproductive age group at a global level. According to many community-based studies, the prevalence of PCOS in India ranges from 3.7 to 22.5% due to the country's enormous population. Upon ultrasound, it shows multiple cysts arranged in a bead of necklace-like appearance causing irregular menstrual cycles and infertility in most cases. It is manifested with abnormally raised testosterone and insulin levels and increased luteinizing hormone (LH)-to-follicle-stimulating hormone (FSH) ratio. Phenotypically, it is presented as obesity, hirsutism, acne and male pattern baldness, which impacts the self-esteem of young girls leading to depression and compromised quality of life. Aim Numerous potential genes have been shown to contribute to PCOS, and the genetic linkage of PCOS has been investigated in many studies. In this study we are looking into the candidate genes, the variants, and other responsible factors behind the genesis of PCOS. This will help in better understanding of its pathogenesis and, as a result, deciphering the mechanism by proper medication. Method of the study We comprehensively searched for publications including PCOS-relevant keywords in different areas in five different electronic databases: PubMed, Google Scholars, Elsevier, Springer Link and Science Direct up to March 2023 focusing on the new ones. We excluded non-English articles, conference papers and studies that were overlapping. Chosen articles were carefully read and further articles that were retrieved from their references were also reviewed so as to make the search complete with the inclusion criterion. Result This review summarizes PCOS as an polygenic and a multifactorial complex disease in which a vast array of genetic and environmental factors are involved. Genes that affect steroidogenesis (ovarian and adrenal), gonadotropin action and regulation, insulin action and secretion, body mass index and chronic inflammation are directly or indirectly associated with PCOS. Conclusion In this study, research of the genetic propensity to PCOS was made, though not in-depth. With the acquired knowledge of array of genes involved, targeted efforts can be made for the potential therapeutic management of the PCOS patients via the novel discovered routes. Moreover, understanding more about PCOS would be beneficial in prevention of the associated metabolic disorders, life-threatening morbidities, restoring fertility and raising the self-esteem of the young women.

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Characterization of DNA Methylation and Screening of Epigenetic Markers in Polycystic Ovary Syndrome

Cited by 3 publications

References 43 publications

Ferroptosis inhibitor ferrostatin‑1 alleviates homocysteine‑induced ovarian granulosa cell injury by regulating TET activity and DNA methylation

Ferroptosis inhibitor ferrostatin‑1 alleviates homocysteine‑induced ovarian granulosa cell injury by regulating TET activity and DNA methylation

Acetate meliorates depressive-like behaviour in a rat model of PCOS through suppression of HDAC2 expression and DNA methylation

Understanding polycystic ovary syndrome in light of associated key genes

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