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BMC Pregnancy and Childbirth
Published in: BMC Pregnancy and Childbirth 1/2024

Open Access 01-12-2024 | Polycystic Ovary Syndrome | Research

Association between single nucleotide polymorphisms, TGF-β1 promoter methylation, and polycystic ovary syndrome

Authors: Mengge Gao, Xiaohua Liu, Heng Gu, Hang Xu, Wenyao Zhong, Xiangcai Wei, Xingming Zhong

Published in: BMC Pregnancy and Childbirth | Issue 1/2024

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Abstract

Background

Polycystic ovarian syndrome (PCOS) is a common endocrine and metabolic disease in women. Hyperandrogenaemia (HA) and insulin resistance (IR) are the basic pathophysiological characteristics of PCOS. The aetiology of PCOS has not been fully identified and is generally believed to be related to the combined effects of genetic, metabolic, internal, and external factors. Current studies have not screened for PCOS susceptibility genes in a large population. Here, we aimed to study the effect of TGF-β1 methylation on the clinical PCOS phenotype.

Methods

In this study, three generations of family members with PCOS with IR as the main characteristic were selected as research subjects. Through whole exome sequencing and bioinformatic analysis, TGF-β1 was screened as the PCOS susceptibility gene in this family. The epigenetic DNA methylation level of TGF-β1 in peripheral blood was detected by heavy sulfite sequencing in patients with PCOS clinically characterised by IR, and the correlation between the DNA methylation level of the TGF-β1 gene and IR was analysed. We explored whether the degree of methylation of this gene affects IR and whether it participates in the occurrence and development of PCOS.

Results

The results of this study suggest that the hypomethylation of the CpG4 and CpG7 sites in the TGF-β1 gene promoter may be involved in the pathogenesis of PCOS IR by affecting the expression of the TGF-β1 gene.

Conclusions

This study provides new insights into the aetiology and pathogenesis of PCOS.
Appendix
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Literature
1.
Qiao J, Li R, Li L. Polycystic ovary syndrome -- an epidemiological study of polycystic ovary syndrome. Chin J Practical Gynecol Obstet. 2013;29(11):849–52.
2.
Roland AV, Nunemaker CS, Keller SR, Moenter SM. Prenatal androgen exposure programs metabolic dysfunction in female mice. J Endocrinol. 2010;207(2):213.PubMedPubMedCentralCrossRef
3.
Risal S, Pei Y, Lu H, Manti M, Stener-Victorin E. Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome. Nat Med. 2019;25(11).
4.
Gorsic LK, Matthew D, Legro RS, Geoffrey HM, Margrit U. Functional genetic variation in the Anti-Müllerian hormone pathway in women with polycystic ovary syndrome. J Clin Endocrinol Metabolism. 2019;7:7.
5.
Crisosto AN, Aldg A, Be A, Mm A, Gc C, Ec D, et al. Higher luteinizing hormone levels associated with antimüllerian hormone in postmenarchal daughters of women with polycystic ovarysyndrome. Fertil Steril. 2019;111(2):381–8.PubMedCrossRef
6.
Jahanfar AJ, Eden, Nguyen LX, Wang et al. A twin study of polycystic ovary syndrome and lipids. Gynecol Endocrinology: Official J Int Soc Gynecol Endocrinol. 1997.
7.
Ning X, Azziz R, Goodarzi MO. Epigenetics in polycystic ovary syndrome: a pilot study of global DNA methylation - ScienceDirect. Fertility & Sterility. 2010;94(2):781–3.CrossRef
8.
Qu F, Wang FF, Yin R, Ding GL, El-Prince M, Gao Q, et al. A molecular mechanism underlying ovarian dysfunction of polycystic ovary syndrome: hyperandrogenism induces epigenetic alterations in the granulosa cells. J Mol Med. 2012;90(8):p911–23.CrossRef
9.
Ray S, Broor SL, Vaishnav Y, Sarkar C, Girish R, Dar L et al. Transforming growth factor beta in hepatitis C virus infection. 2016.
10.
Lee MK, Pardoux C, Hall MC, Lee PS, Warburton D, Qing J, et al. TGF-beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA. EMBO J. 2007;26(17):3957–67.PubMedPubMedCentralCrossRef
11.
Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-β: the master regulator of fibrosis. Nat Rev Nephrol. 2016;12(6):325–38.PubMedCrossRef
12.
Lechuga CG, Hernández-Nazara ZH, Domínguez Rosales JA, Morris ER, Rincón AR, Rivas-Estilla AM, et al. TGF-beta1 modulates matrix metalloproteinase-13 expression in hepatic stellate cells by complex mechanisms involving p38MAPK, PI3-kinase, AKT, and p70S6k. Am J Physiol Gastrointest Liver Physiol. 2004;287(5):G974–87.PubMedCrossRef
13.
Yadav H, Devalaraja S, Chung ST, Rane SG. TGF-β1/Smad3 pathway targets PP2A-AMPK-FoxO1 signaling to regulate hepatic gluconeogenesis. J Biol Chem. 2017;292(8):3420–32.PubMedPubMedCentralCrossRef
14.
Miao ZL, Wang ZN, Yang YD, Chen LQ, Cui R, Wang XL, et al. Role of TGF-β1 in the formation of ovarian interstitial fibrosis in PCOS Rat. Reprod Contracept. 2008;19(002):83–92.CrossRef
15.
Pehlivan. Effects of transforming growth factors-alpha and -beta on proliferation and apoptosis of rat theca-interstitial cells. J Endocrinol. 2001;170(3):639–45.PubMedCrossRef
16.
Escobar-Morreale HF, Luque-Ramírez M, Millán J. The molecular-genetic basis of functional hyperandrogenism and the polycystic ovary syndrome. Endocr Rev. 2005;26(2):251–82.PubMedCrossRef
17.
Zheng X, Price CA, Tremblay Y, Lussier JG, Carriere PD. Role of transforming growth factor-β1 in gene expression and activity of estradiol and progesterone-generating enzymes in FSH-stimulated bovine granulosa cells. Reproduction. 2008;136(4):447.PubMedCrossRef
18.
19.
Christopher B. Immunolocalization of transforming growth factor-beta1 during follicular development and atresia in the mouse ovary. Endocr J. 2000;47(4):475.PubMedCrossRef
20.
Shen H, Wang Y. Activation of TGF-β1/Smad3 signaling pathway inhibits the development of ovarian follicle in polycystic ovary syndrome by promoting apoptosis of granulosa cells. J Cell Physiol. 2019;234(7):11976–85.PubMedCrossRef
21.
Fang Y, Chang HM, Leung PCK, editors. Regulation of transforming growth factor β1(TGF-β1) on the expression and activity of Lysyl oxidase (LOX) in human ovarian granulosa cells2016.
22.
Rosmond R, Chagnon M, Bouchard C, Bj RP. Increased Abdominal Obesity, Insulin and Glucose Levels in Nondiabetic Subjects with a T29C Polymorphism of the Transforming Growth Factor-β1 Gene. Hormone Research in Paediatrics. 2003;59(4):191-4.
23.
Yadav H, Quijano C, Kamaraju A, Gavrilova O, Malek R, Chen W, et al. Protection from obesity and Diabetes by blockade of TGF-β/Smad3 signaling. Cell Metabol. 2011;14(1):67–79.CrossRef
24.
Luo T, Nocon A, Fry J, Sherban A, Rui X, Jiang B, et al. AMPK activation by Metformin suppresses abnormal extracellular matrix remodeling in adipose tissue and ameliorates insulin resistance in obesity. Diabetes. 2016;65(8):2295–310.PubMedPubMedCentralCrossRef
25.
Corradetti MN, Inoki K, Bardeesy N, DePinho RA, Guan KL. Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and peutz-Jeghers syndrome. Genes Dev. 2004;18(13):1533–8.PubMedPubMedCentralCrossRef
26.
Wang X, Xu J. Genomic DNA methylation and histone methylation. Heredity. 2014;36(3):191–9.
27.
LI C, Xing C. Advances in genetic research of polycystic ovary syndrome. J Difficult Dis. 2021.
28.
groxup TREA-sPcw. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). HUMAN REPRODUCTION. 2004.
29.
Amberger JS, Bocchini CA, Schiettecatte F, Scott AF, Hamosh A. OMIM.org: online mendelian inheritance in man (OMIM®), an online catalog of human genes and genetic disorders. (1362–4962 (Electronic)).
30.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. (1530 – 0366 (Electronic)).
31.
Kanehisa M, Furumichi M, Sato Y, Kawashima M, Ishiguro-Watanabe M. KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res. 2023;51(D1):D587–d92.PubMedCrossRef
32.
33.
Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. Omics-a J Integr Biology. 2012;16(5):284–7.CrossRef
34.
Gómez-Rubio V. ggplot2 - Elegant Graphics for Data Analysis (2nd Edition). Journal of Statal Software. 2017;077(Book review 2).
35.
Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the missing heritability of complex Diseases. Nature. 2009;461(7265):747–53.PubMedPubMedCentralCrossRef
36.
Yang J, Zhong T, Xiao G, Chen Y, Liu J, Xia C, et al. Polymorphisms and haplotypes of the TGF-β1 gene are associated with risk of polycystic ovary syndrome in Chinese Han women. Eur J Obstet Gynecol Reproductive Biology. 2015;186:1–7.CrossRef
37.
Raja-Khan R et al. The Role of TGF-β in Polycystic Ovary Syndrome. Reproductive Sciences. 2014;21(1):20–31.
38.
West C, Foster DL, Evans NP, Robinson J, Padmanabhan V. Intra-follicular activin availability is altered in prenatally-androgenized lambs. Mol Cell Endocrinol. 2001;185(1–2):51–9.PubMedCrossRef
39.
Mcneilly AS, Duncan WC. Rodent models of polycystic ovary syndrome. Mol Cell Endocrinol. 2012;373(1–2):2–7.PubMed
40.
Ungefroren H, Groth S, Sebens S, Lehnert H, Gieseler F, Fändrich F. Differential roles of Smad2 and Smad3 in the regulation of TGF-β1-mediated growth inhibition and cell migration in pancreatic ductal adenocarcinoma cells: control by Rac1. Mol Cancer. 2011;10:67.PubMedPubMedCentralCrossRef
41.
Kim KK, Sheppard D, Chapman HA. TGF-β1 signaling and tissue fibrosis. Cold Spring Harb Perspect Biol. 2018;10(4).
42.
Salmeri N, Viganò P, Cavoretto P, Marci R, Candiani M. The kisspeptin system in and beyond reproduction: exploring intricate pathways and potential links between endometriosis and polycystic ovary syndrome. Reviews in endocrine & metabolic disorders; 2023.
43.
Tian J, Al-Odaini AA, Wang Y, Korah J, Dai M, Xiao L, et al. KiSS1 gene as a novel mediator of TGFβ-mediated cell invasion in triple negative Breast cancer. Cell Signal. 2018;42:1–10.PubMedCrossRef
44.
Fang L, Yan Y, Gao Y, Wu Z, Wang Z, Yang S, et al. TGF-β1 inhibits human trophoblast cell invasion by upregulating kisspeptin expression through ERK1/2 but not SMAD signaling pathway. Volume 20. Reproductive biology and endocrinology: RB&E; 2022. p. 22. 1.
45.
Tang R, Ding X, Zhu J. Kisspeptin and Polycystic Ovary Syndrome. Front Endocrinol. 2019;10:298.CrossRef
46.
Ohno H, Shinoda K, Ohyama K, Sharp LZ, Kajimura S. EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex. Nature. 2013;504(7478):163–7.PubMedPubMedCentralCrossRef
47.
Artini PG, Ruggiero M, Parisen Toldin MR, Monteleone P, Monti M, Cela V, et al. Vascular endothelial growth factor and its soluble receptor in patients with polycystic ovary syndrome undergoing IVF. Hum Fertil (Cambridge England). 2009;12(1):40–4.CrossRef
48.
Das M, Djahanbakhch O, Hacihanefioglu B, Saridogan E, Ikram M, Ghali L, et al. Granulosa cell survival and proliferation are altered in polycystic ovary syndrome. J Clin Endocrinol Metab. 2008;93(3):881–7.PubMedCrossRef
49.
Franks S. Polycystic ovary syndrome in adolescents. International journal of obesity (2005). 2008;32(7):1035-41.
50.
Kamat BR, Brown LF, Manseau EJ, Senger DR, Dvorak HF. Expression of vascular permeability factor/vascular endothelial growth factor by human granulosa and theca lutein cells. Role in corpus luteum development. Am J Pathol. 1995;146(1):157–65.PubMedPubMedCentral
51.
Stanek MB, Borman SM, Molskness TA, Larson JM, Stouffer RL, Patton PE. Insulin and insulin-like growth factor stimulation of vascular endothelial growth factor production by luteinized granulosa cells: comparison between polycystic ovarian syndrome (PCOS) and non-PCOS women. J Clin Endocrinol Metab. 2007;92(7):2726–33.PubMedCrossRef
52.
Huang Q, Gong Q, Wen T, Feng S, Xu J, Liu J, et al. Loss of LAMTOR1 in pancreatic β–cells increases glucose–stimulated insulin secretion in mice. Int J Mol Med. 2020;45(1):23–32.PubMed
53.
54.
Moreira TG, Zhang L, Shaulov L, Harel A, Kuss SK, Williams J, et al. Section 13 regulates expression of specific Immune factors involved in inflammation in vivo. Sci Rep. 2015;5:17655.PubMedPubMedCentralCrossRef
55.
de Leon M, Cardenas H, Vieth E, Emerson R, Segar M, Liu Y, et al. Transmembrane protein 88 (TMEM88) promoter hypomethylation is associated with platinum resistance in Ovarian cancer. Gynecol Oncol. 2016;142(3):539–47.PubMedPubMedCentralCrossRef
56.
Irene M, Ivan, Monteleone V. Dinallo, et al. CCL20 Is Negatively Regulated by TGF-β1 in Intestinal Epithelial Cells and Reduced in Crohn’s Disease Patients With a Successful Response to Mongersen, a Smad7 Antisense Oligonucleotide. Journal of Crohns & Colitis; 2016.
57.
Watson CJ, Horgan S, Neary R, Glezeva N, Baugh J. Epigenetic therapy for the treatment of Hypertension-Induced Cardiac Hypertrophy and Fibrosis. J Cardiovasc Pharmacol Therap. 2016;21(1):127–37.CrossRef
58.
Neveu WA, Mills ST, Staitieh BS, Sueblinvong V. TGFβ1 epigenetically modifies Thy-1 expression in primary lung fibroblasts. Am J Physiol Cell Physiol. 2015;309(9):C616.PubMedPubMedCentralCrossRef
59.
Mimouni NEH, Isabel Paiva A-L, Barbotin. Polycystic ovary syndrome is transmitted via a transgenerational epigenetic process. Cell Metabol. 2021;33(3).
60.
Hao D, Yin Q, Zhong X, Wei X, Miao Z. Methylation analysis of anti-mullerian hormone type receptor protein and gene in hyperandrogen PCOS animal model. J Reprod Med. 2016;25(9):6.
61.
Zhong X, Jin F, Huang C, Du M, Gao M, Wei X. DNA methylation of AMHRII and INSR gene is associated with the pathogenesis of polycystic ovary syndrome (PCOS). Technology and health care: official. J Eur Soc Eng Med. 2021;29(S1):11–25.
62.
Tian J, Tian X, Ma S. Expression and significance of IGF-I and TGF-β1 in ovary of polycystic ovary syndrome rats. J Shanxi Med Univ. 2009;40(8):700.
63.
64.
Tabassum F, Jyoti C, Sinha HH, Dhar K, Akhtar MS. Impact of polycystic ovary syndrome on quality of life of women in correlation to age, basal metabolic index, education and marriage. PLoS ONE. 2021;16(3):e0247486.PubMedPubMedCentralCrossRef
Metadata
Title
Association between single nucleotide polymorphisms, TGF-β1 promoter methylation, and polycystic ovary syndrome
Authors
Mengge Gao
Xiaohua Liu
Heng Gu
Hang Xu
Wenyao Zhong
Xiangcai Wei
Xingming Zhong
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Pregnancy and Childbirth / Issue 1/2024
Electronic ISSN: 1471-2393
DOI
https://doi.org/10.1186/s12884-023-06210-3

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