Down-regulation of Long Non-coding RNAs in Reproductive Aging and Analysis of the LncRNA-miRNA-mRNA Networks in Human Cumulus Cells

Overview

Journal J Assist Reprod Genet

Publisher Springer

Specialties Genetics
Reproductive Medicine

Date 2022 Mar 5

PMID 35247118

Authors

Angela Caponnetto

Rosalia Battaglia

Carmen Ferrara

Maria Elena Vento

Placido Borzi

Marianna Paradiso

Paolo Scollo

Michele Purrello

Salvatore Longobardi

Thomas DHooghe

Domenico Valerio

Cinzia Di Pietro

Affiliations

Soon will be listed here.

Abstract

Purpose: Long non-coding RNAs (lncRNAs) control gene expression at multiple levels. By interacting with microRNAs (miRNAs), they regulate their mRNA targets creating dynamic regulatory networks involved in different cellular processes. Their role in follicle development and oocyte maturation has recently emerged. lncRNA deregulation has been found associated with different pathological conditions. In this study, we identified differentially expressed lncRNAs in cumulus cells (CCs) isolated from MII oocytes of advanced maternal age women and proposed ceRNA-networks involved in signaling pathways crucial in ovarian folliculogenesis and female germ cell maturation.

Methods: We performed a high-throughput analysis of the expression profile of 68 lncRNAs from CCs of aged and young women by using NanoString technology. By miRNet, TarPmiR, miRTarBase, OKdb, and KEGG we predicted some ceRNA-networks involving the differentially expressed (DE) lncRNAs, miRNA interactors, and their mRNA target genes.

Results: We identified 28 lncRNAs down-regulated in CC samples from aged women. The analysis revealed that the miRNAs binding 11 of the DE lncRNAs and their mRNA targets are included in ceRNA-networks involved in the regulation of the PI3K-Akt, FOXO, and p53 signaling pathways.

Conclusion: We proposed that the lncRNA down-regulation in CCs from aged women could influence the expression of genes encoding proteins deregulated in reproductive aging. A better understanding of the interplay of lncRNA-miRNA-mRNA networks in human CCs could increase our knowledge about the mechanisms of regulation of gene expression involved in aging, lead to the development of novel therapeutics, and improve reproductive outcomes in aged women.

Citing Articles

Follicular metabolic dysfunction, oocyte aneuploidy and ovarian aging: a review.

Wu D, Liu C, Ding L J Ovarian Res. 2025; 18(1):53.

PMID: 40075456 PMC: 11900476. DOI: 10.1186/s13048-025-01633-2.

Treating Metabolic Dysregulation and Senescence by Caloric Restriction: Killing Two Birds with One Stone?.

Russo L, Babboni S, Andreassi M, Daher J, Canale P, Del Turco S Antioxidants (Basel). 2025; 14(1).

PMID: 39857433 PMC: 11763027. DOI: 10.3390/antiox14010099.

Mitochondria: the epigenetic regulators of ovarian aging and longevity.

Mani S, Srivastava V, Shandilya C, Kaushik A, Singh K Front Endocrinol (Lausanne). 2024; 15:1424826.

PMID: 39605943 PMC: 11598335. DOI: 10.3389/fendo.2024.1424826.

Harnessing the power of miRNAs for precision diagnosis and treatment of male infertility.

Doghish A, Elsakka E, Ahmed Mohamed Moustafa H, Ashraf A, Mageed S, Mohammed O Naunyn Schmiedebergs Arch Pharmacol. 2024; .

PMID: 39535597 DOI: 10.1007/s00210-024-03594-7.

Building a Human Ovarian Antioxidant ceRNA Network "OvAnOx": A Bioinformatic Perspective for Research on Redox-Related Ovarian Functions and Dysfunctions.

Tatone C, Emidio G, Battaglia R, Di Pietro C Antioxidants (Basel). 2024; 13(9).

PMID: 39334761 PMC: 11428640. DOI: 10.3390/antiox13091101.

References

Wang K, Chang H . Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011; 43(6):904-14. PMC: 3199020. DOI: 10.1016/j.molcel.2011.08.018. View

Xu X, Li J, Cao Y, Chen D, Zhang Z, He X . Differential Expression of Long Noncoding RNAs in Human Cumulus Cells Related to Embryo Developmental Potential: A Microarray Analysis. Reprod Sci. 2014; 22(6):672-8. PMC: 4502809. DOI: 10.1177/1933719114561562. View

Li W, Zhang T, Guo L, Huang L . Regulation of PTEN expression by noncoding RNAs. J Exp Clin Cancer Res. 2018; 37(1):223. PMC: 6138891. DOI: 10.1186/s13046-018-0898-9. View

Niu Z, Wang W, Dong X, Tian L . Role of long noncoding RNA-mediated competing endogenous RNA regulatory network in hepatocellular carcinoma. World J Gastroenterol. 2020; 26(29):4240-4260. PMC: 7422540. DOI: 10.3748/wjg.v26.i29.4240. View

Tay Y, Rinn J, Pandolfi P . The multilayered complexity of ceRNA crosstalk and competition. Nature. 2014; 505(7483):344-52. PMC: 4113481. DOI: 10.1038/nature12986. View

McReynolds S, Dzieciatkowska M, McCallie B, Mitchell S, Stevens J, Hansen K . Impact of maternal aging on the molecular signature of human cumulus cells. Fertil Steril. 2012; 98(6):1574-80.e5. DOI: 10.1016/j.fertnstert.2012.08.012. View

DellAversana C, Cuomo F, Longobardi S, DHooghe T, Caprio F, Franci G . Age-related miRNome landscape of cumulus oophorus cells during controlled ovarian stimulation protocols in IVF cycles. Hum Reprod. 2021; 36(5):1310-1325. PMC: 8058597. DOI: 10.1093/humrep/deaa364. View

Carafa V, Nebbioso A, Altucci L . Sirtuins and disease: the road ahead. Front Pharmacol. 2012; 3:4. PMC: 3269041. DOI: 10.3389/fphar.2012.00004. View

Dahariya S, Paddibhatla I, Kumar S, Raghuwanshi S, Pallepati A, Gutti R . Long non-coding RNA: Classification, biogenesis and functions in blood cells. Mol Immunol. 2019; 112:82-92. DOI: 10.1016/j.molimm.2019.04.011. View

10.

Meng L, Teerds K, Tang Z, Zuo B, Hong L . Editorial: Non-coding RNAs in Reproductive Biology. Front Cell Dev Biol. 2021; 9:712467. PMC: 8264356. DOI: 10.3389/fcell.2021.712467. View

11.

Sen R, Ghosal S, Das S, Balti S, Chakrabarti J . Competing endogenous RNA: the key to posttranscriptional regulation. ScientificWorldJournal. 2014; 2014:896206. PMC: 3929601. DOI: 10.1155/2014/896206. View

12.

Andrei D, Nagy R, Van Montfoort A, Tietge U, Terpstra M, Kok K . Differential miRNA Expression Profiles in Cumulus and Mural Granulosa Cells from Human Pre-ovulatory Follicles. Microrna. 2018; 8(1):61-67. PMC: 6340152. DOI: 10.2174/2211536607666180912152618. View

13.

Bolha L, Ravnik-Glavac M, Glavac D . Long Noncoding RNAs as Biomarkers in Cancer. Dis Markers. 2017; 2017:7243968. PMC: 5467329. DOI: 10.1155/2017/7243968. View

14.

Battaglia R, Vento M, Borzi P, Ragusa M, Barbagallo D, Arena D . Non-coding RNAs in the Ovarian Follicle. Front Genet. 2017; 8:57. PMC: 5427069. DOI: 10.3389/fgene.2017.00057. View

15.

Statello L, Guo C, Chen L, Huarte M . Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol. 2020; 22(2):96-118. PMC: 7754182. DOI: 10.1038/s41580-020-00315-9. View

16.

Hutt K, Albertini D . An oocentric view of folliculogenesis and embryogenesis. Reprod Biomed Online. 2007; 14(6):758-64. DOI: 10.1016/s1472-6483(10)60679-7. View

17.

Chen Y, Wang J, Fan Y, Qin C, Xia X, Johnson J . Absence of the long noncoding RNA H19 results in aberrant ovarian STAR and progesterone production. Mol Cell Endocrinol. 2019; 490:15-20. PMC: 6774754. DOI: 10.1016/j.mce.2019.03.009. View

18.

Maidarti M, Anderson R, Telfer E . Crosstalk between PTEN/PI3K/Akt Signalling and DNA Damage in the Oocyte: Implications for Primordial Follicle Activation, Oocyte Quality and Ageing. Cells. 2020; 9(1). PMC: 7016612. DOI: 10.3390/cells9010200. View

19.

Yang J, Qi M, Fei X, Wang X, Wang K . LncRNA H19: A novel oncogene in multiple cancers. Int J Biol Sci. 2021; 17(12):3188-3208. PMC: 8375239. DOI: 10.7150/ijbs.62573. View

20.

Zhang X, Wang W, Zhu W, Dong J, Cheng Y, Yin Z . Mechanisms and Functions of Long Non-Coding RNAs at Multiple Regulatory Levels. Int J Mol Sci. 2019; 20(22). PMC: 6888083. DOI: 10.3390/ijms20225573. View