RGD Reference Report - Gestational choline deficiency causes global and Igf2 gene DNA hypermethylation by up-regulation of Dnmt1 expression. - Rat Genome Database

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Gestational choline deficiency causes global and Igf2 gene DNA hypermethylation by up-regulation of Dnmt1 expression.

Authors: Kovacheva, VP  Mellott, TJ  Davison, JM  Wagner, N  Lopez-Coviella, I  Schnitzler, AC  Blusztajn, JK 
Citation: Kovacheva VP, etal., J Biol Chem. 2007 Oct 26;282(43):31777-88. Epub 2007 Aug 27.
RGD ID: 9588267
Pubmed: PMID:17724018   (View Abstract at PubMed)
DOI: DOI:10.1074/jbc.M705539200   (Journal Full-text)

During gestation there is a high demand for the essential nutrient choline. Adult rats supplemented with choline during embryonic days (E) 11-17 have improved memory performance and do not exhibit age-related memory decline, whereas prenatally choline-deficient animals have memory deficits. Choline, via betaine, provides methyl groups for the production of S-adenosylmethionine, a substrate of DNA methyltransferases (DNMTs). We describe an apparently adaptive epigenomic response to varied gestational choline supply in rat fetal liver and brain. S-Adenosylmethionine levels increased in both organs of E17 fetuses whose mothers consumed a choline-supplemented diet. Surprisingly, global DNA methylation increased in choline-deficient animals, and this was accompanied by overexpression of Dnmt1 mRNA. Previous studies showed that the prenatal choline supply affects the expression of multiple genes, including insulin-like growth factor 2 (Igf2), whose expression is regulated in a DNA methylation-dependent manner. The differentially methylated region 2 of Igf2 was hypermethylated in the liver of E17 choline-deficient fetuses, and this as well as Igf2 mRNA levels correlated with the expression of Dnmt1 and with hypomethylation of a regulatory CpG within the Dnmt1 locus. Moreover, mRNA expression of brain and liver Dnmt3a and methyl CpG-binding domain 2 (Mbd2) protein as well as cerebral Dnmt3l was inversely correlated to the intake of choline. Thus, choline deficiency modulates fetal DNA methylation machinery in a complex fashion that includes hypomethylation of the regulatory CpGs within the Dnmt1 gene, leading to its overexpression and the resultant increased global and gene-specific (e.g. Igf2) DNA methylation. These epigenomic responses to gestational choline supply may initiate the long term developmental changes observed in rats exposed to varied choline intake in utero.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
choline deficiency disease  ISODnmt1 (Rattus norvegicus)9588267; 9588267mRNA:increased expression:liver:RGD 
choline deficiency disease  ISODnmt3l (Rattus norvegicus)9588267; 9588267mRNA:increased expression:liver:RGD 
choline deficiency disease  IDA 9588267; 9588267DNA:hypermethylation:liver:RGD 
choline deficiency disease  IEP 9588267; 9588267; 9588267mRNA:increased expression:liver:RGD 
choline deficiency disease  ISOMbd2 (Rattus norvegicus)9588267; 9588267mRNA:increased expression:liver:RGD 

Objects Annotated

Genes (Rattus norvegicus)
Dnmt1  (DNA methyltransferase 1)
Dnmt3l  (DNA methyltransferase 3 like)
Mbd2  (methyl-CpG binding domain protein 2)

Genes (Mus musculus)
Dnmt1  (DNA methyltransferase 1)
Dnmt3l  (DNA methyltransferase 3-like)
Mbd2  (methyl-CpG binding domain protein 2)

Genes (Homo sapiens)
DNMT1  (DNA methyltransferase 1)
DNMT3L  (DNA methyltransferase 3 like)
MBD2  (methyl-CpG binding domain protein 2)


Additional Information