Skip to main content
SpringerLink
Log in

Upregulated Ribosomal Pathway Impairs Follicle Development in a Polycystic Ovary Syndrome Mouse Model: Differential Gene Expression Analysis of Oocytes

  • Reproductive Endocrinology: Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Polycystic ovary syndrome (PCOS), a common endocrine disorder, is associated with impaired oocyte development, leading to infertility. However, the pathogenesis of PCOS has not been completely elucidated. This study aimed to determine the differentially expressed genes (DEGs) and epigenetic changes in the oocytes from a PCOS mouse model to identify the etiological factors. RNA-sequencing analysis revealed that 90 DEGs were upregulated and 27 DEGs were downregulated in mice with PCOS compared with control mice. DNA methylation analysis revealed 30 hypomethylated and 10 hypermethylated regions in the PCOS group. However, the DNA methylation status did not correlate with differential gene expression. The pathway enrichment analysis revealed that five DEGs (Rps21, Rpl36, Rpl36a, Rpl37a, and Rpl22l1) were enriched in ribosome-related pathways in the oocytes of mice with PCOS, and the immunohistochemical analysis revealed significantly upregulated expression levels of Rps21 and Rpl36. These results suggest that differential gene expression in the oocytes of mice in PCOS is related to impaired folliculogenesis. These findings improve our understanding of PCOS pathogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data Availability

All data sets about RNA-seq and DNA methylation data sets are registered in DDJB (DRA013306 and DRA013300, respectively).

Code Availability

Prism software (Prism 8; GraphPad Software, San Diego, CA, USA).

References

  1. Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Hum Reprod. 2018;33:1602–18.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Shi Y, Zhao H, Shi Y, Cao Y, Yang D, Li Z, et al. Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Nat Genet. 2012;44:1020–5.

    Article  CAS  PubMed  Google Scholar 

  3. Li S, Zhu D, Duan H, Ren A, Glintborg D, Andersen M, et al. Differential DNA methylation patterns of polycystic ovarian syndrome in whole blood of Chinese women. Oncotarget. 2016;8:20656–66.

    Article  PubMed Central  Google Scholar 

  4. Skov V, Glintborg D, Knudsen S, Tan Q, Jensen T, et al. Pioglitazone enhances mitochondrial biogenesis and ribosomal protein biosynthesis in skeletal muscle in polycystic ovary syndrome. PLoS One. 2008;3:e2466.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Jones MR, Brower MA, Xu N, Cui J, Mengesha E, Chen Y-DI. Systems genetics reveals the functional context of PCOS loci and identifies genetic and molecular mechanisms of disease heterogeneity. PLoS Genet. 2015;11:e1005455.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Wang X-X, Wei J-Z, Jiao J, Jiang S-Y, Yu D-H, Li D. Genome-wide DNA methylation and gene expression patterns provide insight into polycystic ovary syndrome development. Oncotarget. 2014;5:6603–10.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Adams J, Liu Z, Ren YA, Wun W-S, Zhou W, Kenigsberg S, et al. Enhanced inflammatory transcriptome in the granulosa cells of women with polycystic ovarian syndrome. J Clin Endocrinol Metab. 2016;101:3459–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Huang X, Pan J, Wu B, Teng X. Construction and analysis of a lncRNA (PWRN2)-mediated ceRNA network reveal its potential roles in oocyte nuclear maturation of patients with PCOS. Reprod Biol Endocrinol. 2018;16:73.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Hayes MG, Urbanek M, Ehrmann DA, Armstrong LL, Lee JY, Sisk R, et al. Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nat Commun. 2015;6:7502.

    Article  CAS  PubMed  Google Scholar 

  10. Day FR, Hinds DA, Tung JY, Stolk L, Styrkarsdottir U, Saxena R, et al. Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome. Nat Commun. 2015;6:8464.

    Article  CAS  PubMed  Google Scholar 

  11. Balen A, Michelmore K. What is polycystic ovary syndrome? Are national views important? Hum Reprod. 2002;17:2219–27.

    Article  PubMed  Google Scholar 

  12. Azziz R, Carmina E, Chen ZJ, Dunaif A, Laven JS, Legro RS, et al. Polycystic ovary syndrome. Nat Rev Dis Primers. 2016;2:16057.

    Article  PubMed  Google Scholar 

  13. Filho FLT, Baracat EC, Lee TH, Suh CS, Matsui M, Chang RJ, et al. Aberrant expression of growth differentiation factor-9 in oocytes of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2002;87:1337–44.

    Article  Google Scholar 

  14. Dumesic DA, Padmanabhan V, Abbott DH. Polycystic ovary syndrome and oocyte developmental competence. Obstet Gynecol Surv. 2008;63:39–48.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Mason HD, Willis DS, Beard RW, Winston RM, Margara R, Franks S. Estradiol production by granulosa cells of normal and polycystic ovaries: relationship to menstrual cycle history and concentrations of gonadotropins and sex steroids in follicular fluid. J Clin Endocrinol Metab. 1994;79:1355–60.

    CAS  PubMed  Google Scholar 

  16. Cordeiro FB, Cataldi TR, de Souza BZ, Rochetti RC, Fraietta R, Labate CA, et al. Hyper response to ovarian stimulation affects the follicular fluid metabolomic profile of women undergoing IVF similarly to polycystic ovary syndrome. Metabolomics. 2018;14:51.

    Article  PubMed  Google Scholar 

  17. Wood JR, Dumesic DA, Abbott DH, Strauss JF 3rd. Molecular abnormalities in oocytes from women with polycystic ovary syndrome revealed by microarray analysis. J Clin Endocrinol Metab. 2007;92:705–13.

    Article  CAS  PubMed  Google Scholar 

  18. Cordeiro FB, Cataldi TR, da Costa LdVT, de Lima CB, Stevanato J, Zylbersztejn DS, et al. Follicular fluid lipid fingerprinting from women with PCOS and hyper response during IVF treatment. J Assist Reprod Genet. 2015;32:45–54.

    Article  PubMed  Google Scholar 

  19. Franks S. Adult polycystic ovary syndrome begins in childhood. Best Pract Res Clin Endocrinol Metab. 2002;16:263–72.

    Article  PubMed  Google Scholar 

  20. Blank SK, Helm KD, McCartney CR, Marshall JC. Polycystic ovary syndrome in adolescence. Ann N Y Acad Sci. 2008;1135:76–84.

    Article  CAS  PubMed  Google Scholar 

  21. Legro RS, Driscoll D, Strauss JF 3rd, Fox J, Dunaif A. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci USA. 1998;95:14956–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Skinner MK, Manikkam M, Guerrero-Bosagna C. Epigenetic transgenerational actions of environmental factors in disease etiology. Trends Endocrinol Metab. 2010;21:214–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nilsson E, Klukovich R, Sadler-Riggleman I, Beck D, Xie Y, Yan W, et al. Environmental toxicant induced epigenetic transgenerational inheritance of ovarian pathology and granulosa cell epigenome and transcriptome alterations: ancestral origins of polycystic ovarian syndrome and primary ovarian insufficiency. Epigenetics. 2018;13:875–95.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Gur EB, Karadeniz M, Turan GA. Fetal programming of polycystic ovary syndrome. World J Diabetes. 2015;6:936–42.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Risal S, Pei Y, Lu H, Manti M, Fornes R, Pui H-P, et al. Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome. Nat Med. 2019;25:1894–904.

    Article  CAS  PubMed  Google Scholar 

  26. Osuka S, Nakanishi N, Murase T, Nakamura T, Goto M, Iwase A, et al. Animal models of polycystic ovary syndrome: a review of hormone-induced rodent models focused on hypothalamus-pituitary-ovary axis and neuropeptides. Reprod Med Biol. 2018;18:151–60.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Heijnen EM, Eijkemans MJ, Hughes EG, Laven JS, Macklon NS, Fauser BC. A meta-analysis of outcomes of conventional IVF in women with polycystic ovary syndrome. Hum Reprod Update. 2005;12:13–21.

    Article  PubMed  Google Scholar 

  28. Caldwell ASL, Middleton LJ, Jimenez M, Desai R, McMahon AC, Allan CM, et al. Characterization of reproductive, metabolic, and endocrine features of polycystic ovary syndrome in female hyperandrogenic mouse models. Endocrinology. 2014;155:3146–59.

    Article  CAS  PubMed  Google Scholar 

  29. Sullivan SD, Moenter SM. Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: implications for a common fertility disorder. Proc Natl Acad Sci USA. 2004;101:7129–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Liao Y, Smyth GK, Shi W. FeatureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30:923–30.

    Article  CAS  PubMed  Google Scholar 

  31. Miura F, Ito T. Highly sensitive targeted methylome sequencing by post-bisulfite adaptor tagging. DNA Res. 2015;22:13–8.

    Article  CAS  PubMed  Google Scholar 

  32. Wu H, Xu T, Feng H, Chen L, Li B, Yao B, et al. Detection of differentially methylated regions from whole-genome bisulfite sequencing data without replicates. Nucleic Acids Res. 2015;43:e141.

    PubMed  PubMed Central  Google Scholar 

  33. Osuka S, Iwase A, Nakahara T, Kondo M, Saito A, Bayasula, et al. Kisspeptin in the hypothalamus of 2 rat models of polycystic ovary syndrome. Endocrinology. 2017;158:367–77.

    CAS  PubMed  Google Scholar 

  34. Ganieva U, Nakamura T, Osuka S, Bayasula Nakanishi N, Kasahara Y, et al. Involvement of transcription factor 21 in the pathogenesis of fibrosis in endometriosis. Am J Pathol. 2020;190:145–57.

    Article  CAS  PubMed  Google Scholar 

  35. Heijnen EMEW, Eijkemans MJC, Hughes EG, Laven JSE, Macklon NS, Fauser BCJM. A meta-analysis of outcomes of conventional IVF in women with polycystic ovary syndrome. Hum Reprod Update. 2006;12:13–21.

    Article  CAS  PubMed  Google Scholar 

  36. Liu L, Rajareddy S, Reddy P, Du C, Jagarlamudi K, Shen Y, et al. Infertility caused by retardation of follicular development in mice with oocyte-specific expression of Foxo3a. Development. 2007;134:199–209.

    Article  CAS  PubMed  Google Scholar 

  37. Bramani S, Song H, Beattie J, Tonner E, Flint DJ, Allan GJ. Amino acids within the extracellular matrix (ECM) binding region (201–218) of rat insulin-like growth factor binding protein (IGFBP)-5 are important determinants in binding IGF-I. J Mol Endocrinol. 1999;23:117–23.

    Article  CAS  PubMed  Google Scholar 

  38. Kwon H, Choi D-H, Bae J-H, Kim J-H, Kim Y-S. mRNA expression pattern of insulin-like growth factor components of granulosa cells and cumulus cells in women with and without polycystic ovary syndrome according to oocyte maturity. Fertil Steril. 2010;94:2417–20.

    Article  CAS  PubMed  Google Scholar 

  39. Wood JR, Dumesic DA, Abbott DH, Strauss JFIII. Molecular abnormalities in oocytes from women with polycystic ovary syndrome revealed by microarray analysis. J Clin Endocrinol Metab. 2007;92:705–13.

    Article  CAS  PubMed  Google Scholar 

  40. McCallie BR, Parks JC, Griffin DK, Schoolcraft WB, Katz-Jaffe MG. Infertility diagnosis has a significant impact on the transcriptome of developing blastocysts. Mol Hum Reprod. 2017;23:549–56.

    Article  CAS  PubMed  Google Scholar 

  41. Ishiguro K-I, Monti M, Akiyama T, Kimura H, Chikazawa-Nohtomi N, Sakota M, et al. Zscan4 is expressed specifically during late meiotic prophase in both spermatogenesis and oogenesis. In Vitro Cell Dev Biol Anim. 2017;53:167–78.

    Article  CAS  PubMed  Google Scholar 

  42. Orisaka M, Tajima K, Tsang BK, Kotsuji F. Oocyte-granulosa-theca cell interactions during preantral follicular development. J Ovarian Res. 2009;2:9.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Zhao SY, Quao J, Chen YJ, Liu P, Li J, Yan J. Expression of growth differentiation factor-9 and bone morphogenetic protein-15 in oocytes and cumulus granulosa cells of patients with polycystic ovary syndrome. Fertil Steril. 2010;94(1):261–7103.

    Article  CAS  PubMed  Google Scholar 

  44. Brogna S, Sato TA, Rosbash M. Ribosome components are associated with sites of transcription. Mol Cell. 2002;10:93–104.

    Article  CAS  PubMed  Google Scholar 

  45. Duncan FE, Jasti S, Paulson A, Kelsh JM, Fegley B, Gerton JL. Age-associated dysregulation of protein metabolism in the mammalian oocyte. Aging Cell. 2017;16:1381–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Liu X-M, Yan M-Q, Ji S-Y, Sha Q-Q, Huang T, Zhao H, et al. Loss of oocyte Rps26 in mice arrests oocyte growth and causes premature ovarian failure. Cell Death Dis. 2018;9:1144.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Takahashi N, Harada M, Hirota Y, Nose E, Azhary JM, Koike H, et al. Activation of endoplasmic reticulum stress in granulosa cells from patients with polycystic ovary syndrome contributes to ovarian fibrosis. Sci Rep. 2017;7:10824.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Rutkowski DT, Kaufman RJ. That which does not kill me makes me stronger: adapting to chronic ER stress. Trends Biochem Sci. 2007;32:469–76.

    Article  CAS  PubMed  Google Scholar 

  49. Drygin D, Lin A, Bliesath J, Ho CB, O’Brien SE, Proffitt C, et al. Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. Cancer Res. 2011;71:1418–30.

    Article  CAS  PubMed  Google Scholar 

  50. Feil R, Fraga MF. Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet. 2012;13:97–109.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was supported by a Grant-in-Aid for Scientific Research (17K16844 to SO) from the Japan Society for the Promotion of Science.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    Natsuki Nakanishi, Satoko Osuka, Bayasula Bayasula, Reina Sonehara, Mayuko Murakami, Sayako Yoshita, Natsuki Miyake, Ayako Muraoka, Yukiyo Kasahara, Tomohiko Murase, Tomoko Nakamura, Maki Goto & Hiroaki Kajiyama

  2. Department of Maternal and Perinatal Medicine, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    Natsuki Nakanishi

  3. Department of Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo, 156-8502, Japan

    Tomohiro Kono, Hisato Kobayashi & Shinya Ikeda

  4. Department of Obstetrics and Gynecology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, 371-8511, Japan

    Akira Iwase

Authors
  1. Natsuki Nakanishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Satoko Osuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tomohiro Kono
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hisato Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shinya Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bayasula Bayasula
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Reina Sonehara
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mayuko Murakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sayako Yoshita
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Natsuki Miyake
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ayako Muraoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yukiyo Kasahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Tomohiko Murase
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Tomoko Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Maki Goto
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Akira Iwase
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Hiroaki Kajiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.I. and S.O. conceptualized and designed the study; N.N., S.O., and T.K. developed the methodology; N.N. and T.K. helped with the animal experiments. N.N. and S.O. prepared the manuscript, analyzed and interpreted the data, and performed statistical analysis; N.N., S.O., B.B., S.Y., S.I., H.Kobayashi, and T.K. provided technical and material support and analyzed the data with assistance from R.S., M.M., N.M., and A.M., and Y.K., T.M., T.N., M.G., and H.Kajiyama supervised the entire project. All authors have read and approved the final version of the manuscript.

Corresponding author

Correspondence to Natsuki Nakanishi.

Ethics declarations

Ethics Approval

The study was approved by the Division of Experimental Animals at Nagoya University Graduate School of Medicine. The ethics committee approval number is 31254.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nakanishi, N., Osuka, S., Kono, T. et al. Upregulated Ribosomal Pathway Impairs Follicle Development in a Polycystic Ovary Syndrome Mouse Model: Differential Gene Expression Analysis of Oocytes. Reprod. Sci. 30, 1306–1315 (2023). https://doi.org/10.1007/s43032-022-01095-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-022-01095-7

Keywords

Search

Navigation