Updates on Molecular Targets and Epigenetic-Based Therapies for PCOS

Smirnov, V. V.; Beeraka, Narasimha M; Butko, Dmitry Yu.; Николенко, В.Н.; Bondarev, Sergey; Ачкасов, Е Е; Sinelnikov, Mikhail Y.; Sinelnikov, P R Hemanth

doi:10.1007/s43032-022-01013-x

Cited by 9 publications

(7 citation statements)

References 127 publications

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“…PCOS is commonly associated with aberrant DNA methylation, and several genes are epigenetically dysregulated, and are associated with the pathological consequences of PCOS and metabolic comorbidities [ 27 ]. However, the methylation status of specific genes and the extent to which genes are dysregulated in terms of methylation patterns are unknown.Due to the reversibility of epigenetic modifications, "druable" regions can be screened to target or correct abnormalities in gene expression, so PCOS methylation promises the development of novel chromatin methylation therapies targeting PCOS [ 28 ].Herein, we used epitranscriptomic microarray for the first time to investigate the altered m 6 A modification of mRNAs and preliminarily explore the potential molecular mechanisms of m 6 A modification in the mouse model of PCOS induced by hyperandrogenism, and to screen new molecular targets and develop effective targets for treating PCOS or inhibiting its progression.…”

Section: Discussionmentioning

confidence: 99%

Alteration of the N6-methyladenosine methylation landscape in a mouse model of polycystic ovary syndrome

Zou,

Li,

et al. 2023

J Ovarian Res

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Objective To explore the N6-methyladenosine (m6A) methylation abnormality of mRNAs and its potential roles in the mouse model of polycystic ovary syndrome (PCOS). Methods The mouse model of PCOS were induced by injecting dehydroepiandrosterone (DHEA), and confirmed by observing the morphological structures of ovarian follicles. Subsequently, m6A-tagged mRNAs were identified via m6A epitranscriptomic microarray and its potential functional pathways were predicted in KEGG database. The expression and modification levels of key mRNAs in the most enriched pathway were evaluated and compared using western blot and methylated RNA immunoprecipitation-quantitative PCR (MeRIP-qPCR). Results Compared with the control group, 415 hypermethylated and downregulated mRNAs, 8 hypomethylated and upregulated mRNAs, and 14 hypermethylated and upregulated mRNAs were identified in the PCOS group (Fold change ≥ 1.5). Those mRNAs were mainly involved in insulin signaling pathway, type II diabetes mellitus, Fc epsilon RI signaling pathway, inositol phosphate metabolism, and GnRH secretion. In insulin signaling pathway, the expression levels of phosphorylated protein kinase B (p-AKT) were decreased, whereas that of upstream phosphorylated phosphatidylinositol 3-kinase (p-PI3K) were increased in PCOS group. Moreover, skeletal muscle and kidney-enriched inositol polyphosphate 5-phosphatease (SKIP), one of PIP3 phosphatases, was verified to be overexpressed, and Skip mRNAs were hypermethylated in PCOS group. Conclusion The altered m6A modification of mRNAs might play a critical role in PCOS process. The PI3K/AKT pathway is inhibited in the mouse model of PCOS. Whether it is caused by the m6A modification of Skip mRNAs is worthy of further exploration.

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Section: Discussionmentioning

confidence: 99%

Alteration of the N6-methyladenosine methylation landscape in a mouse model of polycystic ovary syndrome

Zou,

Li,

et al. 2023

J Ovarian Res

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“…Thus, epigenetic factors should also be considered with regard to their therapeutic potential [ 225 , 226 , 227 ]. The possibility of influencing the processes related to oxidative stress and ROS formation, mitochondrial dysfunction with the release of DAMPs into the cytoplasm, and reversal of the proinflammatory cytokine profile toward normal and elimination of IR may be of high significance [ 37 , 39 , 135 ]. Moreover, effective treatment of the inflammatory background in PCOS can initiate normalization in androgenic activity, thereby removing the major endocrine disorder that limits a patient’s ability to become pregnant [ 148 , 228 ].…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, the participation of epigenetic mechanisms in the etiopathogenesis of PCOS has been a problem attracting increasing attention from researchers [ 34 , 35 , 36 ]. It has been shown beyond reasonable doubt that epigenetic factors are able to initiate and control the inflammatory response and modulate metabolic changes in PCOS, including IR [ 37 , 38 , 39 ]. Importantly, from a therapeutic point of view, unlike genetic changes (e.g., mutations), epigenetic regulation may be reversible because it does not influence DNA sequences [ 40 , 41 ].…”

Section: Introductionmentioning

confidence: 99%

Modulation of the Inflammatory Response in Polycystic Ovary Syndrome (PCOS)—Searching for Epigenetic Factors

Szukiewicz

Trojanowski

Kociszewska

et al. 2022

IJMS

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Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Despite its incidence, the syndrome is poorly understood and remains underdiagnosed, and female patients are diagnosed with a delay. The heterogenous nature of this complex disorder results from the combined occurrence of genetic, environmental, endocrine, and behavioral factors. Primary clinical manifestations of PCOS are derived from the excess of androgens (anovulation, polycystic ovary morphology, lack of or scanty, irregular menstrual periods, acne and hirsutism), whereas the secondary manifestations include multiple metabolic, cardiovascular, and psychological disorders. Dietary and lifestyle factors play important roles in the development and course of PCOS, which suggests strong epigenetic and environmental influences. Many studies have shown a strong association between PCOS and chronic, low-grade inflammation both in the ovarian tissue and throughout the body. In the vast majority of PCOS patients, elevated values of inflammatory markers or their gene markers have been reported. Development of the vicious cycle of the chronic inflammatory state in PCOS is additionally stimulated by hyperinsulinemia and obesity. Changes in DNA methylation, histone acetylation and noncoding RNA levels are presented in this review in the context of oxidative stress, reactive oxygen species, and inflammatory signaling in PCOS. Epigenetic modulation of androgenic activity in response to inflammatory signaling is also discussed.

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“…Attention has therefore been directed at identifying the mechanisms by which lifestyle and environmental exposures alter this regulatory framework (45)(46)(47). A root-cause analysis of the proximate causes of PCOS has identified a wide variety of lifestyle and environmental exposures that are likely to contribute to the pathogenesis of PCOS (1,2,5,48).…”

Section: Introductionmentioning

confidence: 99%

Pathophysiological Effects of Contemporary Lifestyle on Evolutionary-Conserved Survival Mechanisms that Disturb the Hallmarks of Health in Polycystic Ovary Syndrome

Parker¹

2023

Preprint

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Polycystic ovary syndrome (PCOS) is increasingly being characterized as an evolutionary mismatch disorder that presents with a complex mixture of metabolic and endocrine symptoms. The Evolutionary Model proposes that PCOS arises from a collection of inherited polymorphisms that have been consistently demonstrated in a variety of ethnic groups and races. In-utero developmental programming of susceptible genomic variants are thought to predispose the offspring to develop PCOS. Postnatal exposure to lifestyle and environmental risk factors results in epigenetic activation of developmentally programmed genes and disturbance of the hallmarks of health. The resulting pathophysiological changes represent the consequences of poor-quality diet, sedentary behaviour, endocrine disrupting chemicals, stress, circadian disruption, and other lifestyle factors. Emerging evidence suggests that lifestyle-induced gastrointestinal dysbiosis plays a central role in the pathogenesis of PCOS. Lifestyle and environmental exposures initiate changes that result in disturbance of the gastrointestinal microbiome (dysbiosis), immune dysregulation (chronic inflammation), altered metabolism (insulin resistance), endocrine and reproductive imbalance (hyperandrogenism), and central nervous system dysfunction (neuroendocrine, autonomic nervous system). PCOS can be a progressive metabolic condition that leads to obesity, gestational diabetes, type 2 diabetes, metabolic-associated fatty liver disease, metabolic syndrome, cardiovascular disease, and cancer. This review explores the mechanisms that underpin the evolutionary mismatch between ancient survival pathways and contemporary lifestyle factors involved in the pathogenesis and pathophysiology of PCOS.

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Updates on Molecular Targets and Epigenetic-Based Therapies for PCOS

Cited by 9 publications

References 127 publications

Alteration of the N6-methyladenosine methylation landscape in a mouse model of polycystic ovary syndrome

Alteration of the N6-methyladenosine methylation landscape in a mouse model of polycystic ovary syndrome

Modulation of the Inflammatory Response in Polycystic Ovary Syndrome (PCOS)—Searching for Epigenetic Factors

Pathophysiological Effects of Contemporary Lifestyle on Evolutionary-Conserved Survival Mechanisms that Disturb the Hallmarks of Health in Polycystic Ovary Syndrome

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