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Impact d’une carence en vitamines B9 et B12 sur l’épitranscriptome m⁶A et la méthylation des protéines histones

Abstract : Vitamin B9 and B12 are essential micronutrients, notably for brain function, that are brought from green vegetables and animal food respectively. Vitamin B9 and B12 deficiencies are frequent in pregnant women and elderly people. A deficiency is associated with neurological troubles and notably Parkinson’s and Alzheimer’s diseases. At the molecular level, those vitamins are involved in the one carbon metabolism, responsible for the synthesis of S-adenosyl-methionine (SAM). SAM is the universal methyl donor required for almost all the transmethylation reactions, involved in epigenetic regulations. In this work, we propose to investigate 2 different epigenetic modifications: the m⁶A mRNA methylation and histone methylation. m⁶A has recently been shown to be a prevalent mRNA modification. It is notably involved in splicing, translation and miRNA processing. This modification has a mechanism akin to DNA and histone methylations, with a Writer/Reader/Eraser involvement. Here, we developed a first approach to study the m⁶A level depending on B12 availability. A decrease in SAM level resulting from vitamin B12 deficiency was associated with a global decrease of m⁶A level in mRNAs. This was also potentially mediated by a deregulation of the writer complex and an overexpression of the eraser FTO. We further investigated some mRNAs with a role in neurological functions and targeted by YTH reader proteins. Altered m⁶A level could impact mRNA processing in the brain and therefore protein expression, contributing to the neurological phenotype observed following vitamin B12 deficiency. Our results have been confirmed in mice embryonic fibroblasts coming from Cd320-/- mice, CD320 being the receptor for vitamin B12 in the brain. Concerning the histone methylation, we investigated several histone methylation marks in methyl donor deficient rats. We observed a dysregulation of the histone methylation machinery, with an interplay of a cluster of miR. Based on our results, we propose a model explaining how males are less affected by vitamin B9 and B12 deficiency than females, with a strong involvement of epigenetic marks.
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Submitted on : Wednesday, September 8, 2021 - 4:52:05 PM
Last modification on : Thursday, September 9, 2021 - 1:59:35 PM
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Pauline Mosca. Impact d’une carence en vitamines B9 et B12 sur l’épitranscriptome m⁶A et la méthylation des protéines histones. Biochimie, Biologie Moléculaire. Université de Lorraine, 2021. Français. ⟨NNT : 2021LORR0048⟩. ⟨tel-03338505⟩



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