Epigenetic regulation of reproductive potential: from folliculogenesis to implantation

1. Yu X., Xu J., Song B., Zhu R., Liu J., Liu Y.F. et al. The role of epigenetics in women’s reproductive health: The impact of environmental factors. Front. Endocrinol. (Lausanne). 2024; 15: 1399757. https://dx.doi.org/10.3389/fendo.2024.1399757
2. Saftić Martinović L., Mladenić T., Lovrić D., Ostojić S., Dević Pavlić S. Decoding the epigenetics of infertility: mechanisms, environmental influences, and therapeutic strategies. Epigenomes. 2024; 8(3): 34. https://dx.doi.org/10.3390/epigenomes8030034
3. Marsh M.L., Oliveira M.N., Vieira-Potter V.J. Adipocyte metabolism and health after the menopause: the role of exercise. Nutrients. 2023; 15(2): 444. https://dx.doi.org/10.3390/nu15020444
4. Nitsch S., Zorro Shahidian L., Schneider R. Histone acylations and chromatin dynamics: concepts, challenges, and links to metabolism. EMBO Rep. 2021; 22(7): e52774. https://dx.doi.org/10.15252/embr.202152774
5. Wang J., Sun X., Yang Z., Li S., Wang Y., Ren R. et al. Epigenetic regulation in premature ovarian failure: a literature review. Front. Physiol. 2023; 13: 998424. https://dx.doi.org/10.3389/fphys.2022.998424
6. Gong F., Miller K.M. Histone methylation and the DNA damage response. Mutat. Res. Rev. Mutat. Res. 2019; 780: 37-47. https://dx.doi.org/10.1016/j.mrrev.2017.09.003
7. Zama A.M., Uzumcu M. Epigenetic effects of endocrine-disrupting chemicals on female reproduction: an ovarian perspective. Front. Neuroendocrinol. 2010; 31(4): 420-39. https://dx.doi.org/10.1016/j.yfrne.2010.06.003
8. Сыркашева А.Г., Долгушина Н.В., Яроцкая Е.Л. Влияние антропогенных химических веществ на репродукцию. Акушерство и гинекология. 2018; 3: 16-21. [Syrkasheva A.G., Dolgushina N.V., Yarotskaya E.L. The effect of anthropogenic chemicals on reproduction. Obstetrics and Gynecology. 2018; (3): 16-21 (in Russian)]. https://dx.doi.org/10.18565/aig.2018.3.16-21
9. Tricotteaux-Zarqaoui S., Lahimer M., Abou Diwan M., Corona A., Candela P., Cabry R. et al. Endocrine disruptor chemicals exposure and female fertility declining: from pathophysiology to epigenetic risks. Front. Public Health. 2024; 12: 1466967. https://dx.doi.org/10.3389/fpubh.2024.1466967
10. Сыркашева А.Г., Киндышева С.В., Стародубцева Н.Л., Франкевич В.Е., Долгушина Н.В. Бисфенол А в организме пациенток с бесплодием: влияние на результаты программ вспомогательных репродуктивных технологий. Акушерство и гинекология. 2021; 5: 113-20. [Syrkasheva A.G., Kindysheva S.V., Starodubtseva N.L., Frankevich V.E., Dolgushina N.V. Bisphenol A in infertile patients: impact on assisted reproductive technologies outcomes. Obstetrics and Gynecology. 2021; (5): 113-20 (in Russian)]. https://dx.doi.org/10.18565/aig.2021.5.113-120
11. Shi Y.Q., Zhu X.T., Zhang S.N., Ma Y.F., Han Y.H., Jiang Y. et al. Premature ovarian insufficiency: a review on the role of oxidative stress and the application of antioxidants. Front. Endocrinol. (Lausanne). 2023; 14: 1172481. https://dx.doi.org/10.3389/fendo.2023.1172481
12. Throwba H.P.K., Unnikrishnan L., Pangath M., Vasudevan K., Jayaraman S., Li M. et al. The epigenetic correlation among ovarian cancer, endometriosis, and PCOS: a review. Crit. Rev. Oncol. Hematol. 2022; 180: 103852. https://dx.doi.org/10.1016/j.critrevonc.2022.103852
13. Mani S., Srivastava V., Shandilya C., Kaushik A., Singh K.K. Mitochondria: the epigenetic regulators of ovarian aging and longevity. Front. Endocrinol. (Lausanne). 2024; 15: 1424826. https://dx.doi.org/10.3389/fendo.2024.1424826
14. Ju W., Zhao Y., Yu Y., Zhao S., Xiang S., Lian F. Mechanisms of mitochondrial dysfunction in ovarian aging and potential interventions. Front. Endocrinol. (Lausanne). 2024; 15: 1361289. https://dx.doi.org/10.3389/fendo.2024.1361289
15. Xiao C., Fan T., Zheng Y., Tian H., Deng Z., Liu J. et al. H3K4 trimethylation regulates cancer immunity: a promising therapeutic target in combination with immunotherapy. J. Immunother. Cancer. 2023; 11(8): e005693. https://dx.doi.org/10.1136/jitc-2022-005693
16. Wu J., Liu Y., Song Y., Wang L., Ai J., Li K. Aging conundrum: a perspective for ovarian aging. Front. Endocrinol. (Lausanne). 2022; 13: 952471. https://dx.doi.org/10.3389/fendo.2022.952471
17. Wang L., Xu Z., Khawar M.B., Liu C., Li W. The histone codes for meiosis. Reproduction. 2017; 154(3): R65-79. https://dx.doi.org/10.1530/REP-17-0153
18. Ratti M., Lampis A., Ghidini M., Salati M., Mirchev M.B., Valeri N. et al. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) as new tools for cancer therapy: first steps from bench to bedside. Target. Oncol. 2020; 15(3): 261-78. https://dx.doi.org/10.1007/s11523-020-00717-x
19. Shen X., Chen C., Wang Y., Zheng W., Zheng J., Jones A.E. et al. Role of histone variants H2BC1 and H2AZ.2 in H2AK119ub nucleosome organization and polycomb gene silencing. bioRxiv. 2024: Preprint. https://dx.doi.org/10.1101/2024.01.16.575234
20. Usman M., Li A., Wu D., Qinyan Y., Yi L.X., He G. et al. The functional role of lncRNAs as ceRNAs in both ovarian processes and associated diseases. Noncoding RNA Res. 2023; 9(1): 165-77. https://dx.doi.org/10.1016/j.ncrna.2023.11.008
21. ElMonier A.A., El-Boghdady N.A., Fahim S.A., Sabry D., Elsetohy K.A., Shaheen A.A. LncRNA NEAT1 and MALAT1 are involved in polycystic ovary syndrome pathogenesis by functioning as competing endogenous RNAs to control the expression of PCOS-related target genes. Noncoding RNA Res. 2023; 8(2): 263-71. https://dx.doi.org/10.1016/j.ncrna.2023.02.008
22. Loubalova Z., Konstantinidou P., Haase A.D. Themes and variations on piRNA-guided transposon control. Mob. DNA. 2023; 14(1): 10. https://dx.doi.org/10.1186/s13100-023-00298-2
23. Azhar S., Dong D., Shen W.J., Hu Z., Kraemer F.B. The role of miRNAs in regulating adrenal and gonadal steroidogenesis. J. Mol. Endocrinol. 2020; 64(1): R21-43. https://dx.doi.org/10.1530/JME-19-0105
24. Sahafnejad Z., Ramazi S., Allahverdi A. An update of epigenetic drugs for the treatment of cancers and brain diseases: a comprehensive review. Genes. 2023; 14(4): 873. https://dx.doi.org/10.3390/genes14040873
25. Rapani A., Nikiforaki D., Karagkouni D., Sfakianoudis K., Tsioulou P., Grigoriadis S. et al. Reporting on the role of miRNAs and affected pathways on the molecular backbone of ovarian insufficiency: a systematic review and critical analysis mapping of future research. Front. Cell Dev. Biol. 2021; 8: 590106. https://dx.doi.org/10.3389fcell.2020.590106
26. Zhang K., Zhong W., Li W.P., Chen Z.J., Zhang C. miR-15a-5p levels correlate with poor ovarian response in human follicular fluid. Reproduction. 2017; 154(4): 483-96. https://dx.doi.org/10.1530/REP-17-0157
27. Eisenberg I., Nahmias N., Novoselsky Persky M., Greenfield C., Goldman-Wohl D., Hurwitz A. Elevated circulating micro-ribonucleic acid (miRNA)-200b and miRNA-429 levels in anovulatory women. Fertil. Steril. 2017; 107(1): 269-75. https://dx.doi.org/10.1016/j.fertnstert.2016.10.003
28. Chen C.H., Lu F., Yang W.J., Yang P.E., Chen W.M., Kang S.T. et al. A novel platform for discovery of differentially expressed microRNAs in patients with repeated implantation failure. Fertil. Steril. 2021; 116(1): 181-8. https://dx.doi.org/10.1016/j.fertnstert.2021.01.055
29. Wang M., Sun J., Xu B., Chrusciel M., Gao J., Bazert M. et al. Functional characterization of MicroRNA-27a-3p expression in human polycystic ovary syndrome. Endocrinology. 2018; 159(1): 297-309. https://dx.doi.org/10.1210/en.2017-00219
30. Battaglia R., Musumeci P., Ragusa M., Barbagallo D., Scalia M., Zimbone M. et al. Ovarian aging increases small extracellular vesicle CD81+ release in human follicular fluid and influences miRNA profiles. Aging. 2020; 12(12): 12324-41. https://dx.doi.org/10.18632/aging.103441
31. Li L., Shi X., Shi Y., Wang Z. The signaling pathways involved in ovarian follicle development. Front. Physiol. 2021; 12: 730196. https://dx.doi.org/10.3389/fphys.2021.730196
32. Тимофеева A.В., Федоров И.С., Савостина Г.В., Екимов А.Н., Перминова С.Г. Количественный анализ piwiРНК в среде культивирования эуплоидных и анеуплоидных бластоцист как вспомогательный способ отбора качественного эмбриона для переноса в полость матки в программах вспомогательных репродуктивных технологий. Акушерство и гинекология. 2023; 11: 115-30. [Timofeeva A.V., Fedorov I.S., Savostina G.V., Ekimov A.N., Perminova S.G. Quantitative analysis of piwiRNAs in the culture medium of euploid and aneuploid blastocysts as an additional method of selecting a high-quality embryo for transfer to the uterine cavity in assisted reproductive technology programs. Obstetrics and Gynecology. 2023; (11): 115-30 (in Russian)]. https://dx.doi.org/10.18565/aig.2023.180
33. Joseph D.B., Strand D.W., Vezina C.M. DNA methylation in development and disease: An overview for prostate researchers. Am. J. Clin. Exp. Urol. 2018; 6(6): 197-218.
34. Tang Y., Gan H., Wang B., Wang X., Li M., Yang Q. et al. Mediating effects of DNA methylation in the association between sleep quality and infertility among women of childbearing age. BMC Public Health. 2023; 23(1): 1802. https://dx.doi.org/10.1186/s12889-023-16681-w
35. Chen W., Dong L., Wei C., Wu H. Role of epigenetic regulation in diminished ovarian reserve. J. Assist. Reprod. Genet. 2024; 42(2): 389-403. https://dx.doi.org/10.1007/s10815-024-03301-8
36. Glaviano A., Foo A.S.C., Lam H.Y., Yap K.C.H., Jacot W., Jones R.H. et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol. Cancer. 2023; 22(1): 138. https://dx.doi.org/10.1186/s12943-023-01827-6
37. Pelosi E., Omari S., Michel M., Ding J., Amano T., Forabosco A. et al. Constitutively active Foxo3 in oocytes preserves ovarian reserve in mice. Nat. Commun. 2013; 4: 1843. https://dx.doi.org/10.1038/ncomms2861
38. Olsen K.W., Castillo-Fernandez J., Chan A.C., la Cour Freiesleben N., Zedeler A., Bungum M. et al. Identification of a unique epigenetic profile in women with diminished ovarian reserve. Fertil. Steril. 2021; 115(3): 732-41. https://dx.doi.org/10.1016/j.fertnstert.2020.09.009
39. Liu R., Wu J., Guo H., Yao W., Li S., Lu Y. et al. Post-translational modifications of histones: Mechanisms, biological functions, and therapeutic targets. MedComm. 2023; 4(3): e292. https://dx.doi.org/10.1002/mco2.292
40. Handy D.E., Castro R., Loscalzo J. Epigenetic modifications: basic mechanisms and role in cardiovascular disease. Circulation. 2011; 123(19): 2145-56. https://dx.doi.org/10.1161/CIRCULATIONAHA.110.956839
41. Zhu Z., Xu W., Liu L. Ovarian aging: Mechanisms and intervention strategies. Med. Rev. 2022; 2(6): 590-610. https://dx.doi.org/10.1515/mr-2022-0031
42. Xue P., Zhou W., Fan W., Jiang J., Kong C., Zhou W. et al. Increased METTL3-mediated m6A methylation inhibits embryo implantation by repressing HOXA10 expression in recurrent implantation failure. Reprod. Biol. Endocrinol. 2021; 19(1): 187. https://dx.doi.org/10.1186/s12958-021-00872-4
43. Sciorio R., El Hajj N. Epigenetic risks of medically assisted reproduction. J. Clin. Med. 2022; 11(8): 2151. https://dx.doi.org/10.3390/jcm11082151
44. Yang S.C., Park M., Hong K.H., La H., Park C., Wang P. et al. CFP1 governs uterine epigenetic landscapes to intervene in progesterone responses for uterine physiology and suppression of endometriosis. Nat. Commun. 2023; 14(1): 3220. https://dx.doi.org/10.1038/s41467-023-39008-0
45. MacLean J.A., Hayashi K. Progesterone actions and resistance in gynecological disorders. Cells. 2022; 11(4): 647. https://dx.doi.org/10.3390/cells11040647
46. Sindik N., Pereza N., Dević Pavlić S. Epigenetics of oogenesis. Arch. Gynecol. Obs. 2024; 311(2): 183-90. https://dx.doi.org/10.1007/s00404-024-07882-8
47. Chico-Sordo L., García-Velasco J.A. MicroRNAs as biomarkers and therapeutic targets in female infertility. Int. J. Mol. Sci. 2024; 25(23): 12979. https://dx.doi.org/10.3390/ijms252312979
48. Тимофеева А.В., Федоров И.С., Гохберг Я.А., Калинина Е.А. Оценка рецептивности эндометрия по уровню малых некодирующих РНК в маточном аспирате у женщин на фоне циклической гормональной терапии. Акушерство и гинекология. 2023; 7: 90-102. [Timofeeva A.V., Fedorov I.S., Gokhberg Ya.A., Kalinina E.A. Evaluation of endometrial receptivity using the level of small non-coding RNAs in uterine aspirate from women undergoing cyclic hormone therapy. Obstetrics and Gynecology. 2023; (7): 90-102 (in Russian)]. https://dx.doi.org/10.18565/aig.2023.110
49. Шамина М.А., Тимофеева А.В., Калинина Е.А. Малые некодирующие РНК и их потенциальная роль в оценке фертильности супружеской пары в программах вспомогательных репродуктивных технологий. Акушерство и гинекология. 2019; 11: 33-9. [Shamina M.A., Timofeeva A.V., Kalinina E.A. Small non-coding RNAs and their potential role in assessing the fertility of a married couple in assisted reproductive technology programs. Obstetrics and Gynecology. 2019; (11): 33-9 (in Russian)]. https://dx.doi.org/10.18565/aig.2019.11.33-39
50. Тимофеева А.В., Калинина Е.А., Драпкина Ю.С., Чаговец В.В., Макарова Н.П., Сухих Г.Т. Оценка качества эмбриона по профилю экспрессии малых некодирующих РНК в культуральной среде эмбриона в программах вспомогательных репродуктивных технологий. Акушерство и гинекология. 2019; 6: 79-86. [Timofeeva A.V., Kalinina E.A., Drapkina Yu.S., Chagovets V.V., Makarova N.P., Sukhikh G.T. Embryo quality assessment by the small noncoding RNA expression profile in an embryo culture medium in assisted reproductive technology programs. Obstetrics and Gynecology. 2019; (6): 79-86 (in Russian)]. http://dx.doi.org/10.18565/aig.2019.6.79-86

Received 24.06.2025

Accepted 13.11.2025