Epigenetic regulation of transcription: a mechanism for inducing variations in phenotype (fetal programming) by differences in nutrition during early life?

Abstract

There is considerable evidence for the induction of different phenotypes by variations in the early life environment, including nutrition, which in man is associated with a graded risk of metabolic disease; fetal programming. It is likely that the induction of persistent changes to tissue structure and function by differences in the early life environment involves life-long alterations to the regulation of gene transcription. This view is supported by both studies of human subjects and animal models. The mechanism which underlies such changes to gene expression is now beginning to be understood. In the present review we discuss the role of changes in the epigenetic regulation of transcription, specifically DNA methylation and covalent modification of histones, in the induction of an altered phenotype by nutritional constraint in early life. The demonstration of altered epigenetic regulation of genes in phenotype induction suggests the possibility of interventions to modify long-term disease risk associated with unbalanced nutrition in early life.

Fig. 1

Gene silencing by DNA methylation. When CpG dinucleotides are unmethylated in the promoter, RNA polymerase (Pol) can bind and the coding region is transcribed. Methylation of CpGs by the activity of DNA methyl transferases (Dnmt) enables recruitment of methyl CpG binding protein-2 (MeCP2) which in turn recruits the histone deacetylase (HDAC)/ histone methyl transferase (HMT) complex. The HDAC/HMT complex removes acetyl groups from histones and methylates specific lysine residues. The overall effect of DNA and histone methylation is to induce long-term silencing of transcription.

Fig. 2

In euchromatin, packing of histone is loose due to acetylation of lysine residues in the N-terminal domains. This facilitates transcription. Recruitment of the histone deacetylase (HDAC)/ histone methyl transferase (HMT) complex results in deacetylation and methylation of specific lysine residues histones which results in closer packing of histones and transcriptionally inactive heterochromatin.

Fig. 3

The effect of feeding a protein-restricted diet during pregnancy in rats and mice on the methylation status of promoters in the offspring. (A) PPARα promoter methylation status and (B) glucocorticoid receptor (GR) promoter methylation status in the heart of rat offspring on postnatal day 34. (C) PPARα methylation status in rat umbilical cord at post-conceptual day 20. (D) GR promoter methylation status in mouse liver at 3 months after birth. Maternal dietary groups were Control, 18% (w/w) protein; protein-restricted (PR), 9% (w/w) protein; the PR diet supplemented with 5-fold more folic acid (RF). Analysis of promoter methylation was as described by Lillycrop et al. (2005).

Fig. 4

A pathway for induction of altered epigenetic regulation of the expression of specific genes in the offspring of rats fed a protein-restricted (PR) diet during pregnancy. (a) Gene expression is silenced in the early embryo by the activities of DNA methyltransferases (Dnmt) 3a and 3b. (b) In the offspring of rats fed a PR diet, 1-carbon metabolism is impaired either as a direct consequence of the restricted diet or by increased glucocorticoid exposure. This down-regulates Dnmt1 expression (c). Lower Dnmt1 expression results in impaired capacity to methylate hemimethylated DNA during mitosis (d). After sequential mitotic cycles the methylation status of the promoter is reduced and expression is induced in cells which do not express the gene in control animals. Increased gene expression is facilitated by lower binding and expression of methyl CpG binding protein (MeCP)-2 and reduced recruitment of the histone deacetylase (HDAC) / histone methyltransferase (HMT) complex, resulting in higher levels of histone modifications which permit transcription.