title: Sulfamethazine suppresses epigenetic silencing in Arabidopsis by impairing folate synthesis.
abstract: DNA methylation is a critical, dynamically regulated epigenetic mark. Small chemicals can be valuable tools in probing cellular processes, but the set of chemicals with broad effects on epigenetic regulation is very limited. Using the Arabidopsis thaliana repressor of silencing1 mutant, in which transgenes are transcriptionally silenced, we performed chemical genetic screens and found sulfamethazine (SMZ) as a chemical suppressor of epigenetic silencing. SMZ treatment released the silencing of transgenes as well as endogenous transposons and other repetitive elements. Plants treated with SMZ exhibit substantially reduced levels of DNA methylation and histone H3 Lys-9 dimethylation, but heterochromatic siRNA levels were not affected. SMZ is a structural analog and competitive antagonist to p-aminobenzoic acid (PABA), which is a precursor of folates. SMZ decreased the plant folate pool size and caused methyl deficiency, as demonstrated by reductions in S-adenosylmethionine levels and in global DNA methylation. Exogenous application of PABA or compounds downstream in the folate biosynthesis pathway restored transcriptional silencing in SMZ-treated plants. Together, our results revealed a novel type of chemical suppressor of epigenetic silencing, which may serve as a valuable tool for studying the roles and mechanisms of epigenetic regulation and underscores an important linkage between primary metabolism and epigenetic gene regulation.
authors.affiliation: Department of Botany and Plant Sciences, Institute for Integrative Genome Biology, University of California, Riverside, California 92521, USA.
authors.forename: Huiming
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Deng
authors.forename: Daisuke
authors.initials: D
authors.lastname: Miki
authors.forename: Sean
authors.initials: S
authors.lastname: Cutler
authors.forename: Honggui
authors.initials: H
authors.lastname: La
authors.forename: Yueh-Ju
authors.initials: YJ
authors.lastname: Hou
authors.forename: Jeeeun
authors.initials: J
authors.lastname: Oh
authors.forename: Jian-Kang
authors.initials: JK
authors.lastname: Zhu
mesh_terms: D010129:4-Aminobenzoic Acid / Q000494:pharmacology; D017360:Arabidopsis / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D004251:DNA Transposable Elements; D018744:DNA, Plant / Q000378:metabolism; D044127:Epigenesis, Genetic; D005492:Folic Acid / Q000096:biosynthesis*; D018506:Gene Expression Regulation, Plant; D020868:Gene Silencing / Q000187:drug effects*; D006657:Histones / Q000378:metabolism; D008969:Molecular Sequence Data; D030821:Plants, Genetically Modified / Q000235:genetics / Q000378:metabolism; D018749:RNA, Plant / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012436:S-Adenosylmethionine / Q000378:metabolism; D013418:Sulfamethazine / Q000494:pharmacology*; D019076:Transgenes
chemical_list: D004251:DNA Transposable Elements; D018744:DNA, Plant; D006657:Histones; D018749:RNA, Plant; D034741:RNA, Small Interfering; D013418:Sulfamethazine; D012436:S-Adenosylmethionine; D005492:Folic Acid; D010129:4-Aminobenzoic Acid