Cross-talk between miRNAs from the Dlk1-Dio3 locus and histone methylation to protect male cerebellum from methyl donor deficiency
Résumé
Scope: Disruption of the one carbon metabolism during development, i.e. following a gestational vitamin B9 and B12 deficiency, is involved in birth defects and brain development delay. Using a rat nutritional model, consisting of pups born to dams fed a vitamin B9 and B12 deficient diet (MDD), we previously reported molecular and cellular alterations in the brain, in a sex dependent manner, with females being more affected than males. We hypothesized that epigenetic modifications could participate in the sex differences we observed. Methods and Results: We investigated lysine methylation of histones and expression of microRNAs in the cerebellum of MDD male and female pups. We report a differential regulation of H3K36Me2 and H4K20Me3 between males and females, in response to MDD. Moreover, distinct regulation of Kmt5b and Kdm2a expression by miR-134-5p and miR-369-5p from the Dlk1-Dio3 locus, contributes to the maintenance of expression of genes involved in synaptic plasticity. Conclusion: These results could explain the neuroprotection to MDD that male pups display. Our work will contribute to the understanding of the consequences of vitamin starvation on brain development, as well as how the epigenome is affected by one carbon metabolism disruption.
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