MTHFD1 controls DNA methylation in Arabidopsis

Groth, Martin; Moissiard, Guillaume; Wirtz, Markus; Wang, Haifeng; García‐Salinas, Carolina; Ramos-Parra, Perla A.; Bischof, Sylvain; Feng, Suhua; Cokus, Shawn J.; John, Amala; Smith, Danielle C.; Zhai, Jixian; Hale, Christopher J.; Long, J. Bradford De; Hell, Rüdiger; Garza, Rocío I. Díaz de la; Jacobsen, Steven E.

doi:10.1038/ncomms11640

Cited by 59 publications

(48 citation statements)

References 70 publications

(109 reference statements)

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“…Third, the increased SAH in mat4 would compete with SAM and decrease SAM accessibility to methyltransferases, which mostly reduced the CHG and CHH methylation and H3K9me. Similar results have been observed in both fpgs1 and mthfd1 mutants (Zhou et al, 2013;Groth et al, 2016). Both fpgs1 and mthfd1 mutants accumulate relatively more SAH, which leads to a decreased ratio of SAM/SAH (Zhou et al, 2013;Groth et al, 2016).…”

Section: Discussionsupporting

confidence: 80%

“…Treatment with sulfamethazine, which is a structural analog and competitor of p-aminobenzoic acid, the precursor of folate, causes the release of endogenous transposons and repeat elements and the reduction of DNA methylation levels and H3K9me2 (Zhang et al, 2012). A mutation in the cytoplasmic bifunctional methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase (MTHFD1) leads to decreased levels of oxidized tetrahydrofolates, DNA hypomethylation, loss of H3K9me, and transposon reactivation (Groth et al, 2016).…”

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confidence: 99%

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METHIONINE ADENOSYLTRANSFERASE4 Mediates DNA and Histone Methylation

Meng

Wang

et al. 2018

Plant Physiol.

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DNA and histone methylation coregulate heterochromatin formation and gene silencing in animals and plants. To identify factors involved in maintaining gene silencing, we conducted a forward genetic screen for mutants that release the silenced transgene in the transgenic Arabidopsis () line We identified, which encodes methionine (Met) adenosyltransferase 4 (MAT4)/-adenosyl-Met synthetase 3 that catalyzes the synthesis of -adenosyl-Met (SAM) in the one-carbon metabolism cycle. mostly decreases CHG and CHH DNA methylation and histone H3K9me2 and reactivates certain silenced transposons. The exogenous addition of SAM partially rescues the epigenetic defects of SAM content and DNA methylation were reduced more in than in three other mutants. knockout mutations generated by CRISPR/Cas9 were lethal, indicating that is an essential gene in Arabidopsis. MAT1, 2, and 4 proteins exhibited nearly equal activity in an in vitro assay, whereas MAT3 exhibited higher activity. The native promoter driving ,, and cDNA complemented the mutant. However, most transgenic lines carrying native, , and promoters driving cDNA did not complement the mutant because of their lower expression in seedlings. Genetic analyses indicated that the double mutant is dwarfed and the double mutant was nonviable, while showed normal growth and fertility. These results indicate that MAT4 plays a predominant role in SAM production, plant growth, and development. Our findings provide direct evidence of the cooperative actions between metabolism and epigenetic regulation.

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Section: Discussionsupporting

confidence: 80%

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confidence: 99%

METHIONINE ADENOSYLTRANSFERASE4 Mediates DNA and Histone Methylation

Meng

Wang

et al. 2018

Plant Physiol.

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“…However, (i) and (ii) are confounded by the role of CMT3 in maintaining mCHG at transposons and other regions of the genome [25]. (iii) The addition of a methyl group to a cytosine requires the transcription and translation of methyltransferases and protein complexes, and is a biochemical reaction with energetic and metabolic costs [35]. With costs, benefits most likely ensue.…”

Section: Gbm Function Remains Enigmaticmentioning

confidence: 99%

Gene body DNA methylation in plants

Bewick

Schmitz

2017

Current Opinion in Plant Biology

310

320

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The type, amount, and location of DNA methylation within a gene provides pivotal information on the enzymatic pathway by which it was achieved and its functional consequences. In plants (angiosperms specifically), gene body methylation (gbM) refers to genes with an enrichment of CG DNA methylation within the transcribed regions and depletion at the transcriptional start and termination sites. GbM genes often compose the bulk of methylated genes within angiosperm genomes and are enriched for housekeeping functions. Contrary to the transcriptionally repressive effects of other chromatin modifications within gene bodies, gbM genes are constitutively expressed. GbM has intrigued researchers since its discovery, and much effort has been placed on identifying its functional role. Here, we highlight the recent findings on the evolutionary origin and molecular mechanism of gbM and synthesize studies describing the possible roles for this enigmatic epigenetic phenotype.

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“…Intriguingly, this aspect of FOCM could have wider implications, as recently it has been shown that changes to MTHFD1 can affect the regulation of DNA methylation. Groth et al (2016) [102] identified a mutant (mthfd1-1) in Arabidopsis thaliana, which carried a mutation in cytoplasmic MTHFD1. This mutant suffered from accumulation of Hcy and SAM, coupled with extensive genome-wide hypomethylation.…”

Section: Rationale For Computationally Integrating Focm and The Dna Mmentioning

confidence: 99%

Computational modelling folate metabolism and DNA methylation: implications for understanding health and ageing

2016

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Dietary folates have a key role to play in health, as deficiencies in the intake of these B vitamins have been implicated in a wide variety of clinical conditions. The reason for this is folates function as single carbon donors in the synthesis of methionine and nucleotides. Moreover, folates have a vital role to play in the epigenetics of mammalian cells by supplying methyl groups for DNA methylation reactions. Intriguingly, a growing body of experimental evidence suggests that DNA methylation status could be a central modulator of the ageing process. This has important health implications because the methylation status of the human genome could be used to infer age-related disease risk. Thus, it is imperative we further our understanding of the processes which underpin DNA methylation and how these intersect with folate metabolism and ageing. The biochemical and molecular mechanisms, which underpin these processes, are complex. However, computational modelling offers an ideal framework for handling this complexity. A number of computational models have been assembled over the years, but to date, no model has represented the full scope of the interaction between the folate cycle and the reactions, which governs the DNA methylation cycle. In this review, we will discuss several of the models, which have been developed to represent these systems. In addition, we will present a rationale for developing a combined model of folate metabolism and the DNA methylation cycle.

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MTHFD1 controls DNA methylation in Arabidopsis

Cited by 59 publications

References 70 publications

METHIONINE ADENOSYLTRANSFERASE4 Mediates DNA and Histone Methylation

METHIONINE ADENOSYLTRANSFERASE4 Mediates DNA and Histone Methylation

Gene body DNA methylation in plants

Computational modelling folate metabolism and DNA methylation: implications for understanding health and ageing

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