Epitranscriptomic Alteration and Planar Cell Polarity Signaling In Diabetic Embroyopathy

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Pregestational diabetes induces neural tube defects (NTDs) in the offspring. Even under the best preconception care, women having diabetes are still three- to four-times more likely to have a child with a birth defect than women without diabetes. Mechanistic studies provide important insights for the development of novel prevention strategies. Studies using diabetic embryopathy have revealed the critical involvement of epigenetic modifications in the pathogenesis of NTDs. RNA modifications are involved in important biological processes including development. We observed epitranscriptomic changes in neurulation stage embryos exposed to maternal diabetes. Maternal diabetes decreased the expression of the m6A RNA methylation writer’s methyltransferase- like 3 (METTL3) and METTL14 and altered planar cell polarity. Therefore, we hypothesize that maternal diabetes reduces m6A RNA methylation levels by repressing METTL3 and METTL14 expression through oxidative stress responsive kinase signaling in neurulation stage embryos leading to NTDs, and that restoring METTL3 and METTL14 expression in the developing neuroepithelium ameliorates diabetic embryopathy, whereas deleting either one enhances diabetes induced NTDs. Diabetes-induced RNA hypomethylation alters RNA expression encoding the planar cell polarity (PCP) components resulting in neuroepithelial cell polarity defects and cellular dysfunction. Aim 1 will determine the mechanism underlying maternal diabetes reduced METTL3 and METTL14 expression in the developing embryo. We will examine that two transcription factors c-Jun and FOxO3a, which are downstream of the oxidative stress- activated kinase signaling, act in concert in response to maternal diabetes to suppress METTL3 and METTL14 expression in the developing embryos leading to the reduction of m6A RNA methylation in the neuroepithelium. Aim 2 will investigate the critical role of reduced METTL3 and METTL14 expression in the induction of diabetic embryopathy. Our working hypothesis is that restoring either METLL3 or METTL14 in the developing neuroepithelium rescues m6A RNA methylation and ameliorates diabetic embryopathy. Aim 3 will determine whether reduced m6A RNA methylation dysregulates PCP gene expression leading to neuroepithelial cell polarity defects in diabetic embryopathy. We will determine whether maternal diabetes-induced RNA hypomethylation dysregulates PCP mRNA expression leading to disruption of neuroepithelial cell polarity. We will examine whether maternal diabetes increases Fzd5 expression through repressing METLL3 or METTL14.