title: Dietary choline deficiency causes DNA strand breaks and alters epigenetic marks on DNA and histones.
abstract: Dietary choline is an important modulator of gene expression (via epigenetic marks) and of DNA integrity. Choline was discovered to be an essential nutrient for some humans approximately one decade ago. This requirement is diminished in young women because estrogen drives endogenous synthesis of phosphatidylcholine, from which choline can be derived. Almost half of women have a single nucleotide polymorphism that abrogates estrogen-induction of endogenous synthesis, and these women require dietary choline just as do men. In the US, dietary intake of choline is marginal. Choline deficiency in people is associated with liver and muscle dysfunction and damage, with apoptosis, and with increased DNA strand breaks. Several mechanisms explain these modifications to DNA. Choline deficiency increases leakage of reactive oxygen species from mitochondria consequent to altered mitochondrial membrane composition and enhanced fatty acid oxidation. Choline deficiency impairs folate metabolism, resulting in decreased thymidylate synthesis and increased uracil misincorporation into DNA, with strand breaks resulting during error-prone repair attempts. Choline deficiency alters DNA methylation, which alters gene expression for critical genes involved in DNA mismatch repair, resulting in increased mutation rates. Any dietary deficiency which increases mutation rates should be associated with increased risk of cancers, and this is the case for choline deficiency. In rodent models, diets low in choline and methyl-groups result in spontaneous hepatocarcinomas. In human epidemiological studies, there are interesting data that suggest that this also may be the case for humans, especially those with SNPs that increase the dietary requirement for choline.
authors: Nutrition Research Institute, School of Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Kannapolis, NC 28081, United States. steven zeisel@unc.edu
authors: Steven H
authors: SH
authors: Zeisel
mesh_terms: D000818:Animals; D002794:Choline / Q000378:metabolism; D002796:Choline Deficiency / Q000235:genetics*; D053960:DNA Breaks; D004249:DNA Damage; D044127:Epigenesis, Genetic; D042822:Genomic Instability; D006657:Histones / Q000235:genetics*; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics; D009751:Nutritional Requirements
chemical_list: D006657:Histones; D002794:Choline