DNA Methylation and Transcriptional Repression Signaling

Transcriptional repressor proteins associate with their target genes either directly through a DNA-binding domain or indirectly by interacting with other DNA-bound proteins. To inhibit transcription, a repressor protein can mask a transcriptional activation domain or block interaction of an activator with other components of the transcription machinery, or displace an activator from the DNA. DNA response elements exert allosteric effects on transcriptional regulators, which may activate transcription in the context of one gene, yet repress transcription in another.

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Pathway Summary

Transcriptional repressor proteins associate with their target genes either directly through a DNA-binding domain or indirectly by interacting with other DNA-bound proteins. To inhibit transcription, a repressor protein can mask a transcriptional activation domain or block interaction of an activator with other components of the transcription machinery, or displace an activator from the DNA. DNA response elements exert allosteric effects on transcriptional regulators, which may activate transcription in the context of one gene, yet repress transcription in another.DNA methylation interferes with transcription by preventing the binding of basal transcriptional machinery or ubiquitous transcription factors (TFs) that require contact with cytosine (C) in the major groove of the double helix. Transcriptionally active chromatin is predominantly unmethylated and has high levels of acetylated histone tails. Most mammalian TFs have GC-rich binding sites and many have CpGs in their DNA recognition elements. Binding by several of these factors is impeded by methylation of CpG. Methylation at CpG dinucleotides is carried out by one of the three known human DNA methyltransferases (DNMT1, DNMT3a and DNMT3b), resulting in DNA with high levels of CpG methylation, but still containing predominantly acetylated histone tails.CpG methylation induces histone deacetylation, chromatin remodeling and gene silencing through a transcription repressor complex (Sin3A complex) that includes SMRT, mSin3a, RbAp46/48 and the two histone deacetylases HDAC1 and HDAC2 formed around mSin3a. This complex is assembled by interaction of mSin3a with the methyl-binding protein MECP2 and Sin3-Associated Polypeptides 18/30 (SAP18/30). MECP2 acts as a shuttle interlocking DNA methylation and core histone deacetylation in inducing gene silencing. The deacetylase activity, which accompanies the MECP2-bound mSin3a renders the promoter of the gene inaccessible to TFs by deacetylating histone H3 and H4. Another transcription repressor complex (NURD complex) consists of HDAC1 , HDAC2, Mi-2 and methyl-CpG binding domain proteins (MBD). These complexes result in alterations in chromatin structure, producing chromatin that is refractory to transcriptional activation.CpG island methylation is capable of silencing tumor suppressor genes. DNA methylation at the 5-position of cytosine within CpG dinucleotides in mammals is essential for important functions, such as cell differentiation, imprinting and X-inactivation. Several genetic diseases are caused by defects within the methylation machinery, like the Rett syndrome, Fragile X syndrome and Immunodeficiency-centromeric instability-facial anomalies syndrome.

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