Review
Dietary choline deficiency causes DNA strand breaks and alters epigenetic marks on DNA and histones

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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.

Section snippets

Choline requirements

Choline is needed to form membranes (phosphatidylcholine and sphingomyelin are choline-containing phospholipids), it is an important methyl-group donor (choline metabolism intersects with folate metabolism at the methylation of homocysteine to form methionine) and it is needed to form the neurotransmitter acetylcholine [3]. Choline can be made available from endogenous synthesis of phosphatidylcholine in the liver [4], and is a part of the diet; the food sources of choline have been

Choline and oxidative DNA damage

Oxidative damage to DNA, as assessed by the formation of 8-oxodeoxyguanosine [20], [21], apurinic/apyrimidinic sites [22] and Ogg1-sensitive sites [22] in DNA accumulate when rats are deprived of choline. The oxidative stress to DNA is reflected in changes in genes for DNA repair enzymes with significant increases in expression of apurinic/apyrimidinic endonuclease 1 (Ape), poly(ADP-ribose) polymerase 1 (Parp), and DNA polymerase beta (Polβ), 8-oxyguanine DNA glycolase 1 (Ogg1) and

Choline and folate-related DNA damage

Because folate metabolism and choline metabolism are intermingled, perturbing metabolism of choline results in compensatory changes in folate-related metabolic pathways [47], [48], [49]. Thus, diets that are low in choline also result in decreased tissue folate [47], [48]. Folate is a cofactor for metabolic pathways that methylate homocysteine, forming methionine, but also folate is a cofactor for the formation of thymidylate needed for DNA synthesis [19], [50], [51]. When thymine is not

Choline and epigenetic marks

Choline is an important source of methyl-groups for synthesis of S-adenosylmethionine which is needed for epigenetic marking of DNA and histones. [56], [57]. A choline deficient-low methionine diet in rats results in global hypomethylation of hepatic DNA [58]. Choline deficiency also results in altered methylation status of DNA cytosines, usually at repetitive elements such as cytosine-guanine repeats (CpG islands) in the promoters of specific genes [57], [59]. Choline and methyl deficiency can

Choline and cancer

Increased mutation rates are usually associated with increased risk for cancer formation. In addition, as discussed earlier, choline modulates epigenetic marking of genes, and choline deficiency is correlated with the silencing of several tumor suppressor genes responsible for DNA repair (BRCA1, hMLH1) [21], cell cycle regulation (p15, p16) [70] and carcinogen metabolism (GSTP1) [71]. Indeed, choline deficiency is one of the few single nutrient deficiencies that causes increased spontaneous

Conflict of interest

Dr. Zeisel is on the Scientific Advisory Boards for Solae, Hershey, Dupont, and Metabolon.

Funding

Supported by funding from the US National Institutes of Health (DK55865 and DK56350).

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      Citation Excerpt :

      Epigenetic modifications include: (i) DNA methylation, which occurs primarily in the context of cytosine-guanine (CpG) dinucleotides (however a significant portion of methylation is found to be positioned at non-CpG sites particularly in neuronal cells (Lister et al., 2013)) and can influence the spatial structure of the DNA and the binding or the repression of specific DNA-binding proteins (Slatkin, 2009), (ii) histone modifications, which influence the condensation of the DNA around histone proteins and regulate the accessibility of functional regions to transcriptional factors (Tordjman et al., 2014) and (iii) post-transcriptional regulation by non-coding RNAs such as microRNAs (miRNAs) (Issler and Chen, 2015; Luoni and Riva, 2016). Alterations in DNA methylation can, for example, modify the normal development of functional neuronal networks and the differentiation of cells into their normal lineage (Schaevitz and Berger-Sweeney, 2012; Zeisel, 2012) and this has been indeed suggested to underlie the increased risk of developing NDDs (Kundakovic and Jaric, 2017; Lyall et al., 2014a). In the following paragraphs, we report some of the studies that support the presence of long-lasting alterations in the epigenetic machinery in association with early exposures to stress or infections (see Table 5).

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