CpG, methylation

The past few years witnessed some important developments that established a molecular link between CpG methylation and the status of histone acetylation. It was shown that the methyl-binding protein MeCp2 contains a transcriptional repressor domain that interacts directly with the multiprotein corepressor complex mSin3A [84,86]. Antibodies against MeCP2 coprecipitated mSin3A, HDACl and HDAC2, and the deacetylase inhibitor trichostatin A (TSA) relieved the repression. 

The accepted involvement of CpG methylation in transcription regulation has guided various lines of research into the direct effects methylation may have on chromatin structure. As early as 1982, Felsenfeld and co-workers looked for effects of DNA methylation on the affinity of DNA for histone octamers they reported a slight increase in this parameter [163]. Nightingale and Wolffe [164] using mononucleosome reconstitution on a specific sequence, the 5S rDNA from X. borealis, failed to see such an effect. More recently, Travers (personal communication) has seen clear-cut differences in the affinity of the histone octamer for a number of methylated versus unmethylated sequences. The fine structure of the core particle was, however, unaffected by the methylation status of the DNA [165]. 

ChIP-chop allows one to determine if the DNA that is associated with an antigen of interest is highly CpG-methylated. The Escherichia coli enzyme McrBC is used to hydrolyze ( chop ) the DNA that is methylated specifically at purine/cytosine sites. Hydrolysis within the target DNA sequence prevents detection of the DNA by PCR [24]. 

Lodygin D, Tarasov V, Epanchintsev A et al (2008) Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer. CeU Cycle 7 2591-2600... 

Razin, A. CpG methylation, chromatin structure and gene silencing-a three-way connection ... 

Nakayama S, Sasaki A, Mese H, Alcalde RE, Tsuji T, Matsumura T. The E-cadherin gene is silenced by CpG methylation in human oral squamous cell carcinomas. Int J Cancer 2001 93 667-673. 

Methylation of cytosine to form 5-methylcytosine occurs frequently about 70% of CpG dinucleotides in the human genome are methylated. Although not inherited, interest in this 5th base has increased recently as correlations with cancer have been reported. " CpG islands are about 1000 bases in length and are often found near the 5 -end of genes. These regions consist of clusters of CG dinucleotides that are usually not methylated in normal cells. However, CpG methylation correlates with condensed chromatin structure and promoter inactivation an important example occurs in tumor-suppressor genes. 

Cao, H. and Wang, Y. (2007) Quantification of oxidative single-base and intrastrand cross-link lesions in unmethylated and CpG-methylated DNA induced by Fenton-type reagents. Nucleic Acids Res., 35, 4833-4844. 

Although it is not known exactly how CpG methylation inhibits transcription, there is limited evidence that some transcription factors cannot bind to methylated DNA. Another possibility is that transcriptional inhibitory proteins exist in the cell which specifically bind to methylated CpG residues and thereby exclude transcription factors from gene-regulatory regions. 

Both chromatin structure and CpG methylation appear to negatively influence transcription of eukaryotic genes. 

Nucleosomal packing of DNA segments, and CpG methylation in gene regulatory regions, are both associated with... 

Teter B, Finch CE, CondoreUi DF (1994). DNA methylation in the glial fibriUary acidic protein gene map of CpG methylation sites and summary of analysis by restriction enzymes and by LMPCR. J. Neurosci. Res., 39 708-709. 

Yusa K, Takeda J, Horie K (2004) Enhancement of Sleeping Beauty transposition by CpG methylation possible role of heterochromatin formation. Mol Cell Biol 24 4004 018. 

Wenger RH, Kvietikova I, Rolfs A, Camenisch G, Gassmann M. Oxygen-regulated erythropoietin gene expression is dependent on a CpG methylation-fi-ee hypoxia-inducible factor-1 DNA-binding site. Eur J Biochem 1998 253 771-777. 

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