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Deregulation of imprinted genes expression and epigenetic regulators in placental tissue from intrauterine growth restriction

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

Abstract

Purpose

Intrauterine growth restriction (IUGR) is a fetal growth complication that can be caused by ineffective nutrient transfer from the mother to the fetus via the placenta. Abnormal placental development and function have been correlated with abnormal expression of imprinted genes, which are regulated by epigenetic modifications at imprinting control regions (ICRs). In this study, we analyzed the expression of imprinted genes known to be involved in fetal growth and epigenetic regulators involved in DNA methylation, as well as DNA methylation at the KvDMR1 imprinting control region and global levels of DNA hydroxymethylation, in IUGR cases.

Methods

Expression levels of imprinted genes and epigenetic regulators were analyzed in term placental samples from 21 IUGR cases and 9 non-IUGR (control) samples, by RT-qPCR. Additionally, KvDMR1 methylation was analyzed by bisulfite sequencing and combined bisulfite restriction analysis (COBRA) techniques. Moreover, global DNA methylation and hydroxymethylation levels were also measured.

Results

We observed increased expression of PHLDA2, CDKN1C, and PEG10 imprinted genes and of DNMT1, DNMT3A, DNMT3B, and TET3 epigenetic regulators in IUGR placentas. No differences in methylation levels at the KvDMR1 were observed between the IUGR and control groups; similarly, no differences in global DNA methylation and hydromethylation were detected.

Conclusion

Our study shows that deregulation of epigenetic mechanisms, namely increased expression of imprinted genes and epigenetic regulators, might be associated with IUGR etiology. Therefore, this study adds knowledge to the molecular mechanisms underlying IUGR, which may contribute to novel prediction tools and future therapeutic options for the management of IUGR pregnancies.

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Abbreviations

5-hmC:

5-Hydroxymethylcytosine

5-mC:

5-Methylcytosine

DNMT:

DNA methyltransferase

ES cells:

Embryonic stem cells

ICR:

Imprinting control region

IUGR:

Intrauterine growth restriction

TET:

Ten eleven translocation

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Acknowledgments

We thank the obstetricians at the Department of Gynecology/Obstetrics of Hospital São João, Porto, Portugal, for collaboration with sample and patients’ data collection. We are also thankful to members of the Genetics Department of FMUP for technical help and insightful discussions.

Funding

This work was partly funded by the Portuguese Foundation for Science and Technology (FCT) – UID/BIM/04293/2013 and FCT Investigator award to CJM (IF/00047/2012; CEECIND/00371/2017). C.C. is a recipient of a PhD studentship by FCT (SFRH/BD/141855/2018). S.V. is a recipient of a PhD studentship by FCT (SFRH/BD/147440/2019).

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C.C. performed the experiments, analyzed the results, and wrote the first draft of the manuscript; S.V. performed experimental work and revised the manuscript; C.R. (MD, Obstetrician) collected placental samples and patients’ data; C.J.M supervised experimental work, analyzed the data, and wrote the final manuscript; S.D. designed the study, analyzed the data, and wrote the final manuscript. All authors revised and approved the final version of the manuscript.

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Correspondence to C. Joana Marques or Sofia Dória.

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All patients provided a signed informed consent for this study.

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This study was approved by the Health Ethics Committee of Hospital São João/Faculty of Medicine of Porto (N 70/17).

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Caniçais, C., Vasconcelos, S., Ramalho, C. et al. Deregulation of imprinted genes expression and epigenetic regulators in placental tissue from intrauterine growth restriction. J Assist Reprod Genet 38, 791–801 (2021). https://doi.org/10.1007/s10815-020-02047-3

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