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 DNA Methylation and Transcription Repression

DNA is wrapped in superhelicies around nucleosome cores (histone octamers) to form nucleosomes, the basic compaction structures of chromatin. Access to gene promoters is dependent upon the dynamic status of promoter-associated nucleosomes which is controlled by a variety of factors. These include modifications of residues within DNA and post-translational modifications of the histones associated with chromatin structure and proteins of the transcription machinery. Important post-translational modifications of proteins related to gene transcription include acetylation, phosphorylation and methylation. Gene repression through post-translational modification is targeted to specific DNA sites, at least in part, through DNA methylation.

DNA methylation is an epigenetic modification that changes the appearance and structure of DNA without altering its sequence. DNA methylation interferes with the binding of transcriptional machinery by changing recognition sites that involve cytosine, specifically CpG. Many transcription factors require CpG-rich sites to bind to DNA and methylation of these sites interferes with their binding. CpG methylation facilitates the assembly of transcription repressor complexes that contain histone deacetylases, histone methylases and ATPase complexes that mediate chromatin remodeling.

DNA CpG dinucleotide methylation is carried out by DNA methyltransferases such as DNMT1 (DNA (cytosine-5-)-methyltransferase-1), DNMT3a and DNMT3b. Methyl-CpG sites provide binding sites for mCpG-binding proteins involved in gene repression such as MBD1 (methyl-CpG binding domain-1), MBD2 and MeCP2 (methyl CpG binding protein 2). MBD proteins provide links between methylated DNA and specific repressor complexes such as the mSin3a (transcriptional corepressor Sin3a)) and NuRd/Mi2beta(CHD4) complexes via MeCP2 and MBD2, respectively. These corepressor complexes associate with a variety of factors that mediate transcription repression. They contain histone deacetylases (HDAC) that deacetylate histones 3 and 4 of the nucleosome core and restrict access to promoter sites. These complexes also associate with histone methyltransferases and chromatin remodeling ATPase complexes to further modify chromatin and repress gene activity. MBD1 tethers H3 (Lys-9) methylase (Suv39h1), methyl lysine-binding protein (HP1α), histone deacetylase containing complexes to mCpG to facilitate repression via histone deacetylation and methylation.