Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California 90095, USA.
Centre for Organismal Studies, University of Heidelberg, Heidelberg 69120, Germany.
Nat Commun. 2016 Jun 13;7:11640. doi: 10.1038/ncomms11640.
DNA methylation is an epigenetic mechanism that has important functions in transcriptional silencing and is associated with repressive histone methylation (H3K9me). To further investigate silencing mechanisms, we screened a mutagenized Arabidopsis thaliana population for expression of SDCpro-GFP, redundantly controlled by DNA methyltransferases DRM2 and CMT3. Here, we identify the hypomorphic mutant mthfd1-1, carrying a mutation (R175Q) in the cytoplasmic bifunctional methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase (MTHFD1). Decreased levels of oxidized tetrahydrofolates in mthfd1-1 and lethality of loss-of-function demonstrate the essential enzymatic role of MTHFD1 in Arabidopsis. Accumulation of homocysteine and S-adenosylhomocysteine, genome-wide DNA hypomethylation, loss of H3K9me and transposon derepression indicate that S-adenosylmethionine-dependent transmethylation is inhibited in mthfd1-1. Comparative analysis of DNA methylation revealed that the CMT3 and CMT2 pathways involving positive feedback with H3K9me are mostly affected. Our work highlights the sensitivity of epigenetic networks to one-carbon metabolism due to their common S-adenosylmethionine-dependent transmethylation and has implications for human MTHFD1-associated diseases.
DNA 甲基化是一种表观遗传机制，在转录沉默中具有重要功能，并与抑制性组蛋白甲基化（H3K9me）相关。为了进一步研究沉默机制，我们筛选了一个经过诱变的拟南芥群体，以检测 SDCpro-GFP 的表达情况，该基因由 DNA 甲基转移酶 DRM2 和 CMT3 冗余控制。在这里，我们鉴定了一个弱等位突变体 mthfd1-1，其在细胞质双功能亚甲基四氢叶酸脱氢酶/亚甲基四氢叶酸环水解酶（MTHFD1）中携带一个突变（R175Q）。mthfd1-1 中氧化四氢叶酸水平降低和功能丧失致死表明 MTHFD1 在拟南芥中具有必需的酶活性。同型半胱氨酸和 S-腺苷同型半胱氨酸的积累、全基因组 DNA 低甲基化、H3K9me 的丧失和转座子去抑制表明 S-腺苷甲硫氨酸依赖的转甲基作用在 mthfd1-1 中受到抑制。对 DNA 甲基化的比较分析表明，涉及与 H3K9me 正反馈的 CMT3 和 CMT2 途径受到的影响最大。我们的工作强调了由于其共同的 S-腺苷甲硫氨酸依赖的转甲基作用，一碳代谢对表观遗传网络的敏感性，并对人类与 MTHFD1 相关的疾病具有重要意义。
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