Epigenetic mechanisms involved in developmental nutritional programming

Figure 1 Target sequences for DNA methylation studies. The majority of DNA methylation concerns methylcytosine on CpG dinucleotides but recently hydroxymethylcytosine and methylation on non-CpG sites were identified. Non-CpG methylation was reported in gene body, promoters and repetitive elements; its expanse needs to be further investigated. CpG islands (CGI) and gene promoters are preferred targets in many studies as they correspond to a tractable fraction of the genome with obvious regulatory potential. CGIs are defined algorithmically, as sequences with an observed-to-expected ratio of CpG greater than 0.6, a G+C content greater than 0.5 and, in most cases, a length of more than 500 bp. Three classes of promoters were defined according to their CpG content: LCP have the highest probability to be methylated but methylation correlates poorly to transcription, HCP have low probability to be methylated but this correlates with gene expression. However, transcriptional regulation of genes depends also on distal regulatory elements such as enhancers, insulators, locus control regions and silencing elements. In addition, recent studies show that gene-bodies in active transcription sites are enriched in DNA methylation. Moreover, non-promoter CGIs unmethylated regions (UMR) were recently identified, initially unmethylated they become methylated during development in a tissue-specific manner. “CGI shores” sequences were described around CGI, their methylation in normal tissues is highly conserved, tissue-specific and strongly related to gene expression and were highly sensitive to DNA alterations in colon cancer, as opposed to promoters or CGIs. Highly methylated repetitive elements and highly conserved non-coding elements can also be interesting targets for DNA methylation studies. LCG: Low-CpG promoters; ICG: Intermediate-CpG promoters; HCG: High-CpG promoters; HCNE: Highly conserved non-coding elements.