Choline Deficiency, Altered Folate Metabolism, DNA methylation, and Neurogenesis Gene Expression

Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans,Proc Natl Acad Sci U S A. 2005

Individuals who were carriers of the very common 5,10-methylenetetrahydrofolate dehydrogenase-1958A gene allele were more likely than noncarriers to develop signs of choline deficiency (odds ratio, 7.0; 95% confidence interval, 2.0-25; P < 0.01) on the low-choline diet unless they were also treated with a folic acid supplement.


Choline deficiency alters global histone methylation and epigenetic marking at the Re1 site of the calbindin 1 gene.

UNC Nutrition Research Institute at Kannapolis, University of North Carolina, 500 Laureate Way, Kannapolis, NC 28081, USA.

The FASEB Journal (impact factor: 5.71). 09/2009; 24(1):184-95. DOI:10.1096/fj.09-140145

Source: PubMed

ABSTRACT Maternal choline availability is essential for fetal neurogenesis. Choline deprivation (CD) causes hypomethylation of specific CpG islands in genes controlling cell cycling in fetal hippocampus. We now report that, in C57BL/6 mice, CD during gestational days 12-17 also altered methylation of the histone H3 in E17 fetal hippocampi. In the ventricular and subventricular zones, monomethyl-lysine 9 of H3 (H3K9me1) was decreased by 25% (P<0.01), and in the pyramidal layer, dimethyl-lysine 9 of H3 (H3K9me2) was decreased by 37% (P<0.05). These changes were region specific and were not observed in whole-brain preparations. Also, the same effects of CD on H3 methylation were observed in E14 neural progenitor cells (NPCs) in culture. Changes in G9a histone methyltransferase might mediate altered H3K9me2,1. Gene expression of G9a was decreased by 80% in CD NPCs (P<0.001). In CD, H3 was hypomethylated upstream of the RE1 binding site in the calbindin 1 promoter, and 1 CpG site within the calbindin1 promoter was hypermethylated. REST binding to RE1 (recruits G9a) was decreased by 45% (P<0.01) in CD. These changes resulted in increased expression of calbindin 1 in CD (260%; P<0.05). Thus, CD modulates histone methylation in NPCs, and this could underlie the observed changes in neurogenesis.

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

Nutrition Research Institute, School of Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Kannapolis, NC 28081, United States.

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis (impact factor: 2.85). 10/2011; 733(1-2):34-8. DOI:10.1016/j.mrfmmm.2011.10.008

Source: PubMed

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.


Mary E. Resseguie, University of North Carolina at Chapel Hill, 2008 Advisor: Steven H. Zeisel, MD, PhD

“Choline is an essential nutrient for humans, though some of the requirement can be met by endogenous synthesis catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT). ..We found that PEMT transcription was increased in a dose-dependent manner when primary mouse and human hepatocytes were treated with 17-β-estradiol for 24 hours and this increased message was associated with an increase in protein expression and enzyme activity…We suggest that differences in dietary choline requirements occur between men and women because estrogen induces expression of the PEMT gene, allowing premenopausal women to make more choline endogenously…In humans, young women harboring a PEMT promoter SNP are 25X as likely to develop CDS (choline deficiency syndrome) as are non-carriers of this SNP. Here we demonstrate, in human hepatocytes, that a haploblock of SNPs within a key estrogen regulatory region in the PEMT gene disrupt ER-α DNA binding. Hepatocytes homozygous for the risk allele were not estrogen responsive.”

PEMT B promoter SNP, rs12325817, was associated with increased susceptibility to CDS in women (da Costa et al., 2006). Presumably rs12325817 affects transcriptional regulation of the gene or is in linkage disequilibrium (LD) with a SNP that

10affects PEMT function. The SNP was associated with CDS in women but not in men, suggesting that an estrogen regulatory mechanism is involved. Premenopausal women homozygous for the SNP are sensitive, perhaps premenopausal women heterozygous for the rs12325817 risk allele have sufficient estrogen to overcome the effects on estrogen of the single allele, whereas postmenopausal women with lower estrogen levels are sensitive to the SNP and men, with no estrogen, are not sensitive to the SNP at all. This promoter SNP does not fall within a mapped transcription factor binding site nor is it a HapMap (a catalog of common genetic variants that occur in human beings) SNP, which would permit, by imputation, identification of potential regulatory SNPs in linkage disequilibrium with rs12325817 (Frazer et al., 2007). We propose studies to uncover the mechanism whereby rs12325817 or an associated SNP confers risk to CDS. A cSNP that alters the tertiary structure of the active site in PEMT enzyme could potentially decrease the enzyme activity, and people with such a polymorphism would need extra choline for normal liver function. Analogously, a regulatory SNP that affects PEMT gene expression could result in less PEMT message and subsequently less choline availability de novo.

As discussed previously, SNPs that affect choline bioavailability during pregnancy could markedly increase a woman’s risk of having a baby with a birth defect.



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