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Down-regulation of long non-coding RNAs in reproductive aging and analysis of the lncRNA-miRNA-mRNA networks in human cumulus cells

  • Reproductive Physiology and Disease
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

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.

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Acknowledgements

The authors would like to thank the Scientific Bureau of the University of Catania for the language support, the Centro Servizi B.R.I.T. of the University of Catania and Fondi di Ateneo 2020–2022, University of Catania, Open Access line.

Funding

This study was funded by Merck KGaA, Darmstadt, Germany.

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Authors and Affiliations

  1. Department of Biomedical and Biotechnological Sciences, Section of Biology and Genetics “Giovanni Sichel, University of Catania, 95123, Catania, Italy

    Angela Caponnetto, Rosalia Battaglia, Carmen Ferrara, Michele Purrello & Cinzia Di Pietro

  2. IVF Unit, Cannizzaro Hospital, Catania, Italy

    Maria Elena Vento, Placido Borzì, Marianna Paradiso & Paolo Scollo

  3. Global Clinical Development, Merck Serono SpA, Rome, Italy

    Salvatore Longobardi

  4. Global Medical Affairs Fertility, R&D Healthcare, the Healthcare Business of Merck KGaA, Frankfurter Str. 250, 64293, Darmstadt, Germany

    Thomas D’Hooghe

  5. Institute of Genetic Research (IRG), 80143, Naples, Italy

    Domenico Valerio

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  1. Angela Caponnetto
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Italian Society of Embryology, Reproduction, Research (SIERR)

Contributions

A.C. performed the experiments, analyzed and interpreted the data, and wrote the manuscript. R.B. and C.F. performed the experiments and analyzed and interpreted the data. M.E.V., P.B., and M.P. collected the CC samples and clinical data. P.S. and M.P. revised critically the manuscript. S.L. and T.D.H. participated in the study design and revised critically the manuscript. D.V. participated in the study design and coordination. C.D.P. participated in the study design, coordination, data analysis, and interpretation and wrote the manuscript. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Cinzia Di Pietro.

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The authors declare that they have no conflict of interest except S.L. and T.D.H. who are fully employed by Merck KGaA.

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Caponnetto, A., Battaglia, R., Ferrara, C. et al. Down-regulation of long non-coding RNAs in reproductive aging and analysis of the lncRNA-miRNA-mRNA networks in human cumulus cells. J Assist Reprod Genet 39, 919–931 (2022). https://doi.org/10.1007/s10815-022-02446-8

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