Imprinted gene alterations in the kidneys of growth restricted offspring may be mediated by a long non-coding RNA

ABSTRACT

Altered epigenetic mechanisms have been previously reported in growth restricted offspring whose mothers experienced environmental insults during pregnancy in both human and rodent studies. We previously reported changes in the expression of the DNA methyltransferase Dnmt3a and the imprinted genes Cdkn1c (Cyclin-dependent kinase inhibitor 1C) and Kcnq1 (Potassium voltage-gated channel subfamily Q member 1) in the kidney tissue of growth restricted rats whose mothers had uteroplacental insufficiency induced on day 18 of gestation, at both embryonic day 20 (E20) and postnatal day 1 (PN1). To determine the mechanisms responsible for changes in the expression of these imprinted genes, we investigated DNA methylation of KvDMR1, an imprinting control region (ICR) that includes the promoter of the antisense long non-coding RNA Kcnq1ot1 (Kcnq1 opposite strand/antisense transcript 1). Kcnq1ot1 expression decreased by 51% in growth restricted offspring compared to sham at PN1. Interestingly, there was a negative correlation between Kcnq1ot1 and Kcnq1 in the E20 growth restricted group (Spearman’s ρ = 0.014). No correlation was observed between Kcnq1ot1 and Cdkn1c expression in either group at any time point. Additionally, there was a 11.25% decrease in the methylation level at one CpG site within KvDMR1 ICR. This study, together with others in the literature, supports that long non-coding RNAs may mediate changes seen in tissues of growth restricted offspring.

KEYWORDS:

• Intrauterine growth restriction
• uteroplacental insufficiency
• epigenetic mechanisms
• long non-coding RNA
• DNA methylation

Acknowledgments

The authors would like to thank Sandy Khor and Neil Shirley (University of Adelaide) for their help in Qiagility liquid-handling robot programming and setup.

Disclosure statement

No potential conflict of interest was reported by the authors.

Source of support

This research was supported by the National Health and Medical Research Council (NHMRC) of Australia (M.E.W.; 1045602), the Heart Foundation (M.E.W.; G 11 M 5785), a La Trobe University Faculty of Health Sciences Research Grant Award (T.R.), and a Robinson Research Institute (RRI) Seed Grant (T.B-M, M.E.W., and J.F.B.), and supported by the School of Agriculture, Food and Wine, University of Adelaide.

Data availability statement

The data that support the findings of this study are available from the corresponding author ([email protected]) upon request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15592294.2023.2294516

Additional information

Funding

The work was supported by the National Health and Medical Research Council [1045602]; National Heart Foundation of Australia [G 11 M 5785]; La Trobe University Faculty of Health Sciences Research Grant Award Robinson Research Institute [Seed Grant]; Robinson Research Institute [Seed Funding].