Vitamin C boosts DNA demethylation in TET2 germline mutation carriers

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Abstract
Background: Accurate regulation of DNA methylation is necessary for normal cells to differentiate, develop and function. TET2 catalyzes stepwise DNA demethylation in hematopoietic cells. Mutations in the TET2 gene predispose to hematological malignancies by causing DNA methylation overload and aberrant epigenomic landscape. Studies on mice and cell lines show that the function of TET2 is boosted by vitamin C. Thus, by strengthening the demethylation activity of TET2, vitamin C could play a role in the prevention of hematological malignancies in individuals with TET2 dysfunction. We recently identified a family with lymphoma predisposition where a heterozygous truncating germline mutation in TET2 segregated with nodular lymphocyte-predominant Hodgkin lymphoma. The mutation carriers displayed a hypermethylation pattern that was absent in the family members without the mutation. Methods: In a clinical trial of 1 year, we investigated the effects of oral 1 g/day vitamin C supplementation on DNA methylation by analyzing genome-wide DNA methylation and gene expression patterns from the family members. Results: We show that vitamin C reinforces the DNA demethylation cascade, reduces the proportion of hypermethylated loci and diminishes gene expression differences between TET2 mutation carriers and control individuals. Conclusions: These results suggest that vitamin C supplementation increases DNA methylation turnover and provide a basis for further work to examine the potential benefits of vitamin C supplementation in individuals with germline and somatic TET2 mutations. Trial registration: This trial was registered at EudraCT with reference number of 2018-000155-41 (01.04.2019). Graphical
Funding Information
  • Research Council of Finland (312041, 335823)
  • University of Helsinki
  • The Emil Aaltonen Foundation
  • Biomedicum Helsinki-säätiö
  • Orionin Tutkimussäätiö
  • Ida Montinin Säätiö
  • iCAN Digital Precision Cancer Medicine Flagship (320185)
  • Academy Professorship (319083, 320149)

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