DNA methylation of promoters at position 5 of
irak inhibitor in CpG dinucleotides has evolved as an epigenetic mechanism in higher eukaryotes, which proved essential for development, genomic imprinting and inactivation of the X chromosome [1] and [2]. The major outcome of promoter methylation is long-term silencing of the associated genes [3] and [4]. Interest in elucidating the molecular mechanisms of DNA methylation has gained a major momentum in recent years for two main reasons. First, silencing of multiple tumor suppressor genes in many different primary malignancies is frequently correlated with methylation of their promoters [5]. Second, mutations in two key protein factors involved in methylation-mediated silencing including DNA methyltransferase 3b and methyl-CpG binding protein 2 (MeCP2), were found to be responsible for the human diseases ICF (immunodeficiency, centromeric instability and facial anomalies) and Rett syndromes, respectively [6]. In principle, DNA methylation can repress gene transcription either by inhibiting the binding of positive factors to the promoter and/or by recruiting transcriptional co-repressors. However, in general, methylation of CpG islands does not usually impair binding of transcription factors to their cognate elements. The silencing of methylated promoters requires methyl-CpG binding proteins (MBDs) that specifically recognize symmetrically methylated CpG. MBD1 and MBD2 as well as MeCP2 recruit histone deacetylases (HDACs) thereby resulting in repression of gene
expression via of methylation of their promoters.
