Lillycrop, K.A., Slater-Jefferies, J.L., Phillips, E.S., Jackson, A.A., Hanson, M.A. and Burdge, G.C.
The effect of prenatal under-nutrition on the expression of DNA methyltransferases and methyl CPG binding protein 2 in the liver after weaning
Early Human Development, 82, (8(A08)), . (doi:10.1016/j.earlhumdev.2006.06.003).
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Induction of an altered metabolic phenotype
in the offspring of rats fed a protein-restricted (PR) diet
during pregnancy involves hypomethylation and increased expression of the hepatic glucocorticoid receptor (GR) and
PPARa promoters. To determine the mechanism responsible
for promoter hypomethylation we investigated the effect
of feeding a PR diet to pregnant rats on the expression of
DNA methyltransferase (DMNT)-1 which maintains DNA
methylation during mitosis, DNMT 3a and 3b which catalyse
DNA methylation de novo, the DNA demethylase MBD2 and
the methyl CpG binding protein (MeCP)-2 which recruits
enzymes that regulate covalent histone modifications to
methylated DNA in the liver of the adult offspring.
Methods: Rats were fed either a control or PR diet from
conception to delivery, and chow during lactation. Offspring
were weaned onto chow at postnatal day 28 and
killed at postnatal day 34. mRNA expression was determined
by real-time quantitative RT PCR.
Results: There was no effect of prenatal under-nutrition on
the expression of DNMT 3a or 3b, or on the expression of
MBD2. DNMT1 expression was significantly lower (17%,
p b0.05) and MeCP2 expression was reduced (28.6%,
p b0.05) in the PR offspring vs. controls.
Discussion: These results suggest that prenatal undernutrition
induces hypomethylation of the PPARa and GR
promoters by reducing the capacity of DNMT1 to methylate
hemimethylated DNA during mitosis. Thus induction of an
altered phenotype by prenatal under-nutrition may be the
result of impaired DNMT1 activity. Lower MeCP2 expression,
together with hypomethylation of CpGs, may facilitate
histone acetylation leading to increased transcription.
Disclosure: Was this work supported by industry? No.
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