MTHFD1 controls DNA methylation in Arabidopsis.
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.
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California 90095, USA.
Martin
0000-0003-0547-5032
M
Groth
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California 90095, USA.
Guillaume
G
Moissiard
Centre for Organismal Studies, University of Heidelberg, Heidelberg 69120, Germany.
Markus
0000-0001-7790-4022
M
Wirtz
Basic Forestry and Proteomics Research Center, Haixia Institute of Science and Technology (HIST), Fujian Province Key Laboratory of Plant Virology, Institute of Plant Virology, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, China.
Haifeng
H
Wang
Tecnologico de Monterrey, Campus Monterrey, Ave. Eugenio Garza Sada 2501, Monterrey 64849, México.
Carolina
C
Garcia-Salinas
Tecnologico de Monterrey, Campus Monterrey, Ave. Eugenio Garza Sada 2501, Monterrey 64849, México.
Perla A
PA
Ramos-Parra
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California 90095, USA.
Sylvain
S
Bischof
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California 90095, USA.|Eli &Edythe Broad Center of Regenerative Medicine &Stem Cell Research, University of California Los Angeles, Los Angeles, California 90095, USA.|Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, California 90095, USA.
Suhua
S
Feng
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California 90095, USA.
Shawn J
SJ
Cokus
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California 90095, USA.
Amala
A
John
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California 90095, USA.
Danielle C
DC
Smith
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California 90095, USA.
Jixian
J
Zhai
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California 90095, USA.
Christopher J
CJ
Hale
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California 90095, USA.
Jeff A
JA
Long
Centre for Organismal Studies, University of Heidelberg, Heidelberg 69120, Germany.
Ruediger
R
Hell
Tecnologico de Monterrey, Campus Monterrey, Ave. Eugenio Garza Sada 2501, Monterrey 64849, México.
Rocío I
RI
Díaz de la Garza
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California 90095, USA.|Eli &Edythe Broad Center of Regenerative Medicine &Stem Cell Research, University of California Los Angeles, Los Angeles, California 90095, USA.|Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, California 90095, USA.
Steven E
SE
Jacobsen
D017360:Arabidopsis / Q000235:genetics*; D029681:Arabidopsis Proteins / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D000073399:DNA Demethylation; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D005492:Folic Acid / Q000378:metabolism; D018506:Gene Expression Regulation, Plant / Q000187:drug effects; D020868:Gene Silencing; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D008239:Lysine / Q000378:metabolism; D045064:Methenyltetrahydrofolate Cyclohydrolase / Q000235:genetics / Q000378:metabolism*; D008715:Methionine / Q000494:pharmacology; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects; D012436:S-Adenosylmethionine / Q000378:metabolism; D013763:Tetrahydrofolates / Q000494:pharmacology
D029681:Arabidopsis Proteins; D006657:Histones; D013763:Tetrahydrofolates; C013123:5,10-methylenetetrahydrofolic acid; D049452:Green Fluorescent Proteins; D012436:S-Adenosylmethionine; D005492:Folic Acid; D008715:Methionine; C000628164:MTHFD1 protein, Arabidopsis; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D045064:Methenyltetrahydrofolate Cyclohydrolase; D008239:Lysine