Université de Lorraine, Inserm, NGERE, Nancy, F-54000, France.
CINJ, Rutgers Cancer Institute of New Jersey, 195 Little Albany St, New Brunswick, NJ 08901, USA.
Mol Nutr Food Res. 2023 Nov;67(21):e2300040. doi: 10.1002/mnfr.202300040. Epub 2023 Sep 6.
Disruption of the one carbon metabolism during development, i.e., following a gestational vitamin B9 and B12 deficiencies, 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), the study previously reports molecular and cellular alterations in the brain, in a sex dependent manner, with females being more affected than males. The study hypothesizes that epigenetic modifications could participate in the sex differences is observed.
The study investigates lysine methylation of histones and expression of microRNAs in the cerebellum of MDD male and female pups. The study reports 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.
These results could explain the neuroprotection to MDD that male pups display. The 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.
在发育过程中（即妊娠期间维生素 B9 和 B12 缺乏），一碳代谢的破坏与出生缺陷和大脑发育迟缓有关。本研究使用了一种大鼠营养模型，由喂食维生素 B9 和 B12 缺乏饮食的母鼠所生的幼崽组成，该模型以前的研究报告了大脑中的分子和细胞改变，这些改变具有性别依赖性，雌性比雄性受到的影响更大。该研究假设表观遗传修饰可能参与了观察到的性别差异。
本研究调查了 MDD 雄性和雌性幼崽小脑组织中组蛋白赖氨酸甲基化和 microRNA 的表达。研究报告称，H3K36Me2 和 H4K20Me3 在雄性和雌性中存在差异调节，以响应 MDD。此外，来自 Dlk1-Dio3 基因座的 miR-134-5p 和 miR-369-5p 对 Kmt5b 和 Kdm2a 表达的不同调节，有助于维持参与突触可塑性的基因的表达。
这些结果可以解释雄性幼崽对 MDD 的神经保护作用。这项工作将有助于理解维生素饥饿对大脑发育的影响，以及表观基因组如何受到一碳代谢破坏的影响。
