Mechanisms of transcriptional repression by DNA methylation

Tumorigenesis is known to be a multistep process in which defects in various cancer genes accumulate. Epigenetic modifications, most importantly DNA methylation events, are frequently involved in transcriptional changes in both tumor suppressor genes and oncogenes. Methylation of cytosine at CpG dinucleotides is a common feature of a higher eukaryotic genomes. DNA methylation in the promoter regions of genes is generally correlated with gene silencing. Two underlying mechanisms have been identified. First, binding of transcription factors or enhancer blocking elements, such as CTCF, may be inhibited by DNA methylation. The second and more general mechanism involves proteins that detect methylated DNA through methyl CpG-binding domains (MBDs). Four of these proteins桵BD1, MBD2, MBD3, and MeCP2梙ave been implicated in methylation-dependent repression of transcription. These proteins mediate recruitment of repressor complexes that include histone deacetylases (HDACs). HDACs remove acetyl groups from lysine residues of histones H3 and H4 that results in condensation of chromatin and thus limit access of transcription factors to promoter regions of genes localized nearby. Well-studied co-repressor complexes include Sin3A and Mi-2/NuRD. MeCP2, a polypeptide characterized by an MBD and a transcriptional repression domain that specifically binds methylated DNA, copurifies with the Sin3A/HDAC corepressor complex. MeCP1 complex is composed of 10 major polypeptides including MBD2 and all of the known NuRD complex components. The two protein complexes share four polypeptides: HDAC1, HDAC2, RbAp46, and RbAp48. In addition, each complex contains unique polypeptides (Sin3A, SAP30, and SAP18 in the Sin3 complex, and Mi2, MTA1, MTA2 and MBD3 in the NuRD complex). The NuRD complex possesses nucleosome remodeling activity because of the presence of Mi2, a member of the SWI2/SNF2 helicase/ ATPase family. This complex preferentially binds, remodels, and deacetylates methylated nucleosomes. MTA1 or MTA2 (metastasis-associated protein 1 or 2) expression levels are elevated in metastatic cancer cells, MTA2 modulates the enzymatic activity of the histone deacetylase core complex.

Contributor: A. Konev, PhD

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