MTHFD1 controls DNA methylation in Arabidopsis

• Published in: Nature communications 2016-06, Vol.7 (1), p.11640-13, Article 11640
• Main Authors: Groth, Martin, Moissiard, Guillaume, Wirtz, Markus, Wang, Haifeng, Garcia-Salinas, Carolina, Ramos-Parra, Perla A., Bischof, Sylvain, Feng, Suhua, Cokus, Shawn J., John, Amala, Smith, Danielle C., Zhai, Jixian, Hale, Christopher J., Long, Jeff A., Hell, Ruediger, Díaz de la Garza, Rocío I., Jacobsen, Steven E.
• Format: Article
• Language: English
• Subjects: 13; 631/337/176/1988; 631/449/1659; 631/45/607/1168; Arabidopsis - genetics; Arabidopsis Proteins - genetics; Arabidopsis Proteins - metabolism; Cytoplasm - drug effects; Cytoplasm - metabolism; Dehydrogenases; DNA Demethylation; DNA methylation; DNA Methylation - genetics; Epigenesis, Genetic; Epigenetics; Folic Acid - metabolism; Gene Expression Regulation, Plant - drug effects; Gene Silencing; Genomes; Green Fluorescent Proteins - metabolism; Histones - metabolism; Homeostasis - drug effects; Homocysteine; Humanities and Social Sciences; Lysine - metabolism; Metabolism; Methenyltetrahydrofolate Cyclohydrolase - genetics; Methenyltetrahydrofolate Cyclohydrolase - metabolism; Methionine - pharmacology; Methylenetetrahydrofolate Dehydrogenase (NADP) - genetics; Methylenetetrahydrofolate Dehydrogenase (NADP) - metabolism; Models, Biological; multidisciplinary; Mutation; Mutation - genetics; Protein Transport - drug effects; RNA polymerase; S-Adenosylmethionine - metabolism; Science; Science (multidisciplinary); Tetrahydrofolates - pharmacology; Virology
• ISSN: 2041-1723; 2041-1723
• 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 methylation contributes to transcriptional silencing. Here, Groth et al. show that mutant plants defective in MTHFD1, an enzyme involved in folate metabolism, have a DNA hypomethylation phenotype highlighting the link between one-carbon metabolism and DNA methylation, which is mediated by SAM as a common methyl donor.