期刊
MOLECULAR NUTRITION & FOOD RESEARCH
卷 60, 期 4, 页码 949-956出版社
WILEY
DOI: 10.1002/mnfr.201500819
关键词
Folate deficiency; Folic acid over-supplementation; Impaired folate metabolism; Polymorphisms; RNAi
资金
- Faculty of Life Sciences, University of Vienna
ScopeImpaired folate metabolism increases the risk of birth defects, neurodegenerative and cardiovascular disease, osteoporosis and cancer. We used Caenorhabditis elegans to investigate impaired folate metabolism by RNA interference of key enzymes in the methionine synthase (MS) and thymidylate synthase (TS) cycle and by folate deficiency and over-supplementation feeding studies. Methods and resultsFolate status is influenced by genetic variations (polymorphisms), folate deficiency and supplementation. Single RNAi of dihydrofolate reductase (DHFR), methylenetetrahydrofolate reductase (MTHFR) and MS revealed that gene regulation is largely affected in both folate cycles. Adaptation requires a close transcriptional connection between TS and MS cycle. Coupled DHFR and MS expression is required to balance both cycles, but seems to reduce the overall rate of folate conversion. Feeding studies showed that folate over-supplementation to functioning metabolism inactivates MS and MTHFR expression and enhances TS activity, which favors DNA synthesis over methylation reactions. Folate deficiency disrupted homeostasis by favoring TS cycle and led to malformation in C. elegans offspring. Embryos show aneuploidy and are nonviable lacking DNA repair during meiotic stage of diakinesis. ConclusionSingle gene silencing alters gene expression in both cycles and disrupts folate homeostasis. Folate over-supplementation and deficiency favors TS over MS cycle and causes prophase DNA damage.
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