Aberrant Expression and DNA Methylation of Lipid Metabolism Genes in PCOS: a New Insight into Its Pathogenesis

Overview

Journal Clin Epigenetics

Publisher Biomed Central

Specialty Genetics

Date 2018 Jan 19

PMID 29344314

Citations 34

Authors

Jie-Xue Pan

Ya-Jing Tan

Fang-Fang Wang

Ning-Ning Hou

Yu-Qian Xiang

Jun-Yu Zhang

Ye Liu

Fan Qu

Qing Meng

Jian Xu

Jian-Zhong Sheng

He-Feng Huang

Affiliations

Soon will be listed here.

Abstract

Background: Polycystic ovary syndrome (PCOS), whose etiology remains uncertain, is a highly heterogenous and genetically complex endocrine disorder. The aim of this study was to identify differentially expressed genes (DEGs) in granulosa cells (GCs) from PCOS patients and make epigenetic insights into the pathogenesis of PCOS.

Results: Included in this study were 110 women with PCOS and 119 women with normal ovulatory cycles undergoing in vitro fertilization acting as the control group. RNA-seq identified 92 DEGs unique to PCOS GCs in comparison with the control group. Bioinformatic analysis indicated that synthesis of lipids and steroids was activated in PCOS GCs. 5-Methylcytosine analysis demonstrated that there was an approximate 25% reduction in global DNA methylation of GCs in PCOS women (4.44 ± 0.65%) compared with the controls (6.07 ± 0.72%; < 0.05). Using MassArray EpiTYPER quantitative DNA methylation analysis, we also found hypomethylation of several gene promoters related to lipid and steroid synthesis, which might result in the aberrant expression of these genes.

Conclusions: Our results suggest that hypomethylated genes related to the synthesis of lipid and steroid may dysregulate expression of these genes and promote synthesis of steroid hormones including androgen, which could partially explain mechanisms of hyperandrogenism in PCOS.

Citing Articles

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References

Morgan H, Santos F, Green K, Dean W, Reik W . Epigenetic reprogramming in mammals. Hum Mol Genet. 2005; 14 Spec No 1:R47-58. DOI: 10.1093/hmg/ddi114. View

Eden A, Gaudet F, Waghmare A, Jaenisch R . Chromosomal instability and tumors promoted by DNA hypomethylation. Science. 2003; 300(5618):455. DOI: 10.1126/science.1083557. View

Miller W . Molecular biology of steroid hormone synthesis. Endocr Rev. 1988; 9(3):295-318. DOI: 10.1210/edrv-9-3-295. View

Sang Q, Li X, Wang H, Wang H, Zhang S, Feng R . Quantitative methylation level of the EPHX1 promoter in peripheral blood DNA is associated with polycystic ovary syndrome. PLoS One. 2014; 9(2):e88013. PMC: 3914883. DOI: 10.1371/journal.pone.0088013. View

Kaur S, Archer K, Devi M, Kriplani A, Strauss 3rd J, Singh R . Differential gene expression in granulosa cells from polycystic ovary syndrome patients with and without insulin resistance: identification of susceptibility gene sets through network analysis. J Clin Endocrinol Metab. 2012; 97(10):E2016-21. PMC: 3674289. DOI: 10.1210/jc.2011-3441. View

Matsuzaki K, Deng G, Tanaka H, Kakar S, Miura S, Kim Y . The relationship between global methylation level, loss of heterozygosity, and microsatellite instability in sporadic colorectal cancer. Clin Cancer Res. 2005; 11(24 Pt 1):8564-9. DOI: 10.1158/1078-0432.CCR-05-0859. View

Karpf A, Matsui S . Genetic disruption of cytosine DNA methyltransferase enzymes induces chromosomal instability in human cancer cells. Cancer Res. 2005; 65(19):8635-9. DOI: 10.1158/0008-5472.CAN-05-1961. View

Urbanek M, Legro R, Driscoll D, Azziz R, Ehrmann D, Norman R . Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence for linkage is with follistatin. Proc Natl Acad Sci U S A. 1999; 96(15):8573-8. PMC: 17558. DOI: 10.1073/pnas.96.15.8573. View

Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M . Autophagy regulates lipid metabolism. Nature. 2009; 458(7242):1131-5. PMC: 2676208. DOI: 10.1038/nature07976. View

10.

Ishida A, Mutoh T, Ueyama T, Bando H, Masubuchi S, Nakahara D . Light activates the adrenal gland: timing of gene expression and glucocorticoid release. Cell Metab. 2005; 2(5):297-307. DOI: 10.1016/j.cmet.2005.09.009. View

11.

Xiang Y, Zhang X, Li Q, Xu J, Zhou X, Wang T . Promoter hypomethylation of TIMP3 is associated with pre-eclampsia in a Chinese population. Mol Hum Reprod. 2012; 19(3):153-9. DOI: 10.1093/molehr/gas054. View

12.

Trapnell C, Pachter L, Salzberg S . TopHat: discovering splice junctions with RNA-Seq. Bioinformatics. 2009; 25(9):1105-11. PMC: 2672628. DOI: 10.1093/bioinformatics/btp120. View

13.

Doi S, Al-Zaid M, Towers P, Scott C, Al-Shoumer K . Steroidogenic alterations and adrenal androgen excess in PCOS. Steroids. 2006; 71(9):751-9. DOI: 10.1016/j.steroids.2006.05.005. View

14.

Yu Y, Sun C, Liu Y, Li Y, Wang L, Zhang W . Promoter methylation of CYP19A1 gene in Chinese polycystic ovary syndrome patients. Gynecol Obstet Invest. 2013; 76(4):209-13. DOI: 10.1159/000355314. View

15.

Gleyzer N, Vercauteren K, Scarpulla R . Control of mitochondrial transcription specificity factors (TFB1M and TFB2M) by nuclear respiratory factors (NRF-1 and NRF-2) and PGC-1 family coactivators. Mol Cell Biol. 2005; 25(4):1354-66. PMC: 548005. DOI: 10.1128/MCB.25.4.1354-1366.2005. View

16.

Dunning K, Cashman K, Russell D, Thompson J, Norman R, Robker R . Beta-oxidation is essential for mouse oocyte developmental competence and early embryo development. Biol Reprod. 2010; 83(6):909-18. DOI: 10.1095/biolreprod.110.084145. View

17.

Schneider E, Pliushch G, El Hajj N, Galetzka D, Puhl A, Schorsch M . Spatial, temporal and interindividual epigenetic variation of functionally important DNA methylation patterns. Nucleic Acids Res. 2010; 38(12):3880-90. PMC: 2896520. DOI: 10.1093/nar/gkq126. View

18.

Humphries A, Weller J, Klein D, Baler R, Carter D . NGFI-B (Nurr77/Nr4a1) orphan nuclear receptor in rat pinealocytes: circadian expression involves an adrenergic-cyclic AMP mechanism. J Neurochem. 2004; 91(4):946-55. DOI: 10.1111/j.1471-4159.2004.02777.x. View

19.

Downs S, Mosey J, Klinger J . Fatty acid oxidation and meiotic resumption in mouse oocytes. Mol Reprod Dev. 2009; 76(9):844-53. PMC: 3995453. DOI: 10.1002/mrd.21047. View

20.

Sen A, Hammes S . Granulosa cell-specific androgen receptors are critical regulators of ovarian development and function. Mol Endocrinol. 2010; 24(7):1393-403. PMC: 2903904. DOI: 10.1210/me.2010-0006. View