REVIEW ARTICLE Biological Sciences (An (An International Journal of Medical, Pharmaceutical, and Life Sciences) Journal available at: http://www.biolsciences.periodikos.com.br Importance of biological clock epigenetics in the manifestation of polycystic ovary syndrome Ziaur Rahman1, Mohd Rabi Bazaz1, Tulasi Pasam1, Mani Surya Kumar1, Manoj P. Dandekar1* 1Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, India ARTICLE HISTORY ABSTRACT Received: 19-04-2021 In recent times, the incidence of polycystic ovary syndrome Revised: 21-04-2021 (PCOS) increases at an alarming rate. It is ascribed to the Accepted: 21-04-2021 metabolic and endocrine imbalance, which subsequently Online: 24-04-2021 adversely impacts the fertility of women. Growing evidence indicates the crucial role of circadian biology in the development KEYWORDS and progression of PCOS. Here, we describe the role of epigenetic machinery related to circadian genes (Clock, Bmal, Polycystic ovary syndrome Per, and Cry) on insulin resistance and hyperandrogenism Epigenetics components of the PCOS. We comprehensively discuss the Circadian rhythm interconnection between the genetics of circadian rhythm and DNA methylation PCOS pathophysiology. Deeper insights into the epigenetic Histone modification changes of circadian genes may open new routes for the MicroRNA epigenetic regulation of ovarian physiology and PCOS. Introduction of women (2,3). The infertility rate is 70-80% in women with PCOS (4). Multiple studies reported that women with PCOS have a 2.7-fold increased Polycystic ovary syndrome (PCOS) is an endocrine risk for developing endometrial cancer. However, and metabolic ailment in women characterized by the risk of ovarian and breast cancer remains hyperandrogenism, ovulatory disorder, polycystic unchanged (5). The risk factors for PCOS include ovarian morphology (PCOM), and hyperinsulinemia genetic changes, insulin resistance (IR), (1). In premenopausal women, PCOS occurrence hyperinsulinemia, hyperandrogenism, ovarian ranges from 6~20%, indicating the endocrine and follicular maturation arrest, gonadotropic metabolic origin of the sickness at reproductive age derangements, and obesity (1,3). The daily 24 h sleep-wake cycle is maintained by circadian rhythm, *Address for correspondence involved in directing various endogenous Department of Pharmacology & Toxicology, National physiological, metabolic functions, and genetic Institute of Pharmaceutical Education and Research expressions (6). The circadian rhythm controls the (NIPER), Balanagar, Hyderabad, Telangana, India metabolic activity, as distressed circadian rhythm is Email: [email protected] connected with various metabolic syndromes like diabetes, insulin resistance, and obesity (7). Sleep http://doi-ds.org/doilink/04.2021- disturbances and sleep apnoea increase the PCOS 72777975/biolsci080121 incidence by two-fold (8). The two well-known Published by IR Research Publication; Rahman Z et biomarkers of the circadian cycle are cortisol and al © 2021 by Biological Sciences is licensed under CC BY melatonin, as cortisol peaks in the early morning and melatonin levels rise in the night. Interestingly, 4.0 Rahman Z et al 2021 Biological Sciences, 2021, Vol. 01, Page 67-81 Abbreviations: AR: Androgen receptor; Bmal: Brain and muscle ARNT-like protein; BMI: Body mass index; CK: Casein kinases; Clock: Circadian locomotor output cycles kaput; CREB: cAMP response element binding protein; Cry: Cryptochrome; DAX: Nuclear receptor subfamily; DNMT: DNA methyltransferase; EPHX: Epoxide hydrolase; ESR: Estrogen receptor; EZH: Zeste homolog ; FOXL: Forkhead Box L; FSH: Follicle stimulating hormone; GLUT: Glucose transporter type; GnRH: Gonadotropin-releasing hormone; HAT: Histone acetyltransferases; HDAC: Histone deacetylase; HDM: Histone demethylase; HFD: High-fat diet; HGC: Human chorionic gonadotropin; HMGA: high-mobility group AT; HMT: Histone methyl transferase; HOMA-IR: Homeostatic model assessment for insulin resistance; HSD3B: 3-beta-hydroxysteroid dehydrogenase; IER: Immediate early response; IGF1R: Insulin like growth factor 1 receptor; INSR: Insulin receptor; IR: Insulin resistance; IRS: Insulin receptor substrate; LH: Luteinising hormone ; MeDIP: Methylated DNA immunoprecipitation; miRNA: MicroRNA; MTNR: Melatonin receptor; NAD: Nicotinamide-adenine dinucleotide; NCOR: nuclear corepressor; NPAS: Neuronal Per-Arnt-Sim domain-containing protein; ORP: Oxysterol-binding protein-related protein; PCOM: Polycystic ovarian morphology; PCOS: Polycystic ovary syndrome; Per: Period ; PPAR : peroxisome proliferator-initiated receptor gamma; PTEN: Phosphatase and tensin homolog; SCN: Suprachiasmatic nuclei; SF: Steroidogenic factor; SNP: Single- nucleotide polymorphism; SRD5A: 3-oxo-5α-steroid 4-dehydrogenase; STAR: Steroidogenic acute regulatory protein; T2DM:Type 2 diabetes mellitus women with PCOS showed an elevated level of describe the interconnection of these two systems in melatonin in the morning, which indicates a the development and progression of PCOS. disturbed circadian cycle. The rise of cortisol levels in PCOS subjects might indicate stress‐mediated Epigenetics hyperactivity of the hypothalamus‐pituitary‐adrenal (HPA) axis (9). A typical component of PCOS is a disturbance of neuroendocrine and endocrine The altered epigenetic programming has been function, suggesting sporadic cycles and timing of associated with various diseases, including diabetes ovarian steroid hormone discharge (10). Changes in (14) and prostate cancer (15). Since PCOS is the clock gene expression in the ovary may occur concurrently seen with both reproductive and due to the hormonal imbalances associated with metabolic abnormalities (16,17), the epigenetic these disorders (11). Hyperandrogenemia prompts mechanisms may be critical in this phenomenon. a dramatic change in the timing system, especially Epigenetic changes are generally assessed by DNA clock gene expression in the ovarian follicle and liver methylation, histone modifications, and RNA- (12). This impact on the timing of ovarian clock gene related silencing (25). Aberrations in the epigenome expression may intensify the adverse effects of contribute to numerous ailments etiology, both abundant androgen on key segments of the steroid prenatal and postnatal life (26). biosynthetic and ovulatory response pathways (13). Dysfunctional epigenetic machinery has been noted DNA Methylation as a pertinent factor in several diseases such as obesity and diabetes (14), and prostate cancer (15). DNA methylation can be presented as a biomarker PCOS, being a common denominator for both for epigenetic modification. Epigenetic alteration by reproductive and metabolic abnormalities, may also DNA methylation in the mammalian genome be epigenetically regulated (16,17). Emerging includes methyl group switch at the cytosine C5 studies suspected the role of circadian epigenetic in position to produce 5-methylcytosine. Noteworthy, the development of PCOS (18–22). A higher level of a massive number of DNMTs have been global DNA methylation was reported in PCOS- differentially methylated in adipose tissue of women overweight patients (23). miRNA is expressed with PCOS (27). The unaltered total methylation was differently in PCOS linked with several other reported in PCOS patients with the global DNA mechanisms such as insulin signaling, inflammation, methylation examinations on peripheral blood adipogenesis, and hyperandrogenemia (24). In leukocytes (28). In further studies, higher global PCOS, ovarian dysfunction with hyperandrogenism methylated DNA levels in PCOS patients and also is associated with the alteration of HDAC3. Several harbored a bounty of additional hypermethylated PPAR agonists such as pioglitazone and CpG locales. Thus, DNA methylation may enhance rosiglitazone significantly mitigate the function of a gene in PCOS ovary granulosa cells hyperandrogenism and improve ovulation rates in (23). The genome-wide methylated DNA PCOS women. Treatment with PPAR agonist also immunoprecipitation (MeDIP) has been used to suggested resuming the normal ovarian function. identify abnormally methylated genes in patients Thus, downregulation of PPARꝩ1 expression in the with PCOS. Seventy-nine genes were abnormally granulosa cells (GCs) and induction of ovarian methylated in PCOS-non-IR versus PCOS-IR dysfunction in PCOS patients may be due to patients, and 40 genes were abnormally methylated hyperandrogenism. The epigenetic alterations of in PCOS sufferers than healthy controls (28,29). PPARꝩ1 may lead to ovarian dysfunction induced by Moreover, hyperandrogenism has been connected hyperandrogenism. However, since epigenetic with the methylation status of genes indispensable changes in the circadian genes with respect to for ordinary reproduction and ovarian capacity. For PCOS incidence are poorly discussed, herein we instance, a study carried out in hyperandrogenic females revealed 2 hypermethylated and 5 Biol Sci ©2021 All rights reserved Rahman Z et al 2021 Biological Sciences, 2021, Vol. 01, Page 67-81 hypomethylated CpG sites in the PPAR 1 and phenotype's progression (45). Long et al. (2014) nuclear corepressor 1 (NCOR1) promoter regions confirmed that miR-222, miR-146a, and miR-30c (30). In another study, Sang et al. (2014) determined might additionally serve as novel biomarkers for the methylation degree of each CpG site in the PCOS diagnosis. A genome-wide association study promoter of epoxide