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.