Gene expression/regulation methylation

In higher eukaiyotes, most of the chromosomal DNA carries 5-methyl-cytidine residues located in CpG sequence motives. There is a close correlation between transcriptional inactivation and methylation. On the other hand, considerable evidence shows that regions of DNA that are actively engaged in transcription lack 5-methyl-cytidine nucleotides in CpG motivs. Hence DNA methylation is a means how cells regulate gene expression. DNA methylation which is catalyzed by DNA methyltransferases is the best characterized epigenetic mechanism. 

Bestor, T. (1990), DNA methylation evolution of a bacterial immune function into a regulator of gene expression and genome structure in higher eukaryotes , Philosophical Transactions of the Royal Society of London, Series B, 326 179- 187. 

Shi Y, Lan L, Matson C, Mulhgan P, Whetstine JR, Cole PA, Casero RA, Shi Y (2004) Histone demethylation mediated by the nuclear amine oxidase homolog LSDl. Cell 119 941-953 Shilatifard A (2006) Chromatin Modifications by Methylation and Ubiquitination Implications in the Regulation of Gene Expression. Annu Rev Biochem 75 243-269 Sterner DE, Berger SL (2000) Acetylation of histones and transcription-related factors. Microbiol. Mol Biol Rev 64 435-459... 

In eukaryotes, DNA methylation is important in regulation of gene function. The predominant prodnct of methylation in the DNA of vertebrates is 5-methylcytosine. This methylated base is found largely in CG dinucleotides in palindromic sequences. These may occur in control regions upstream of transcribed DNA sequences. There is considerable evidence to strongly suggest that DNA methylation in vertebrates turns off gene expression. 

MLL (also named ALL-1, HRX, and HTRX), the human homolog of Drosophila trithorax, is a SET domain protein that methylates H3 at Lys-4. The enzymatic activity was enhanced with H3 acetylated at Lys-9 or Lys-14. MLL is a component of a large multiprotein complex composed of greater than 29 proteins, including TFIID, SWI/SNF remodeling complex and NuRD, a histone deacetylase complex. MLL binds to the promoter of Hox genes and regulates their expression [202,203]. 

Org, T. et al. (2008) Peterson, The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EM BO Reports, 9, 370-376. 

Histone methylation participates in the regulation of gene expression patterns. Unlike histone acetylation, histone methylation does not alter the charge of the amino acid and hence the histone tail. There are changes in the basicity and the hydrophobicity which are relatively small when viewed at the scale of the histone but still influence the affinity of the histone tails to certain proteins, for example transcription factors, which in turn result in certain signaling events. The histone methyltransferases are usually subdivided into three classes SET domain lysine methyltransfeases, nonSET domain lysine methyltransferases and arginine methyltransferases (PRMTs). All of them utilize S-adenosylmethionine (SAM) as cosubstrate for the methylation reaction... 

Histones are basic proteins that are made up by a globular domain and an N-terminal tail that protrudes from the nucleosome. Nucleosomes form the basic unit of chromatin and are made up by a complex of DNA wrapped around an octamer of histones formed by pairs of the histones H2A, H2B, H3, and H4 (45,46) (Fig. 1). Post-translational modification of the core histone tails by methylation, acetylation, phosphorylation, ubiquitina-tion, or sumoylation can alter the structure of the nucleosomes and thus alter gene expression. These post-translational modifications determine the structure and pattern of chromatin condensation and determine the histone code that drives gene transcriptional regulation (47,48). Below are briefly described the factors determining the histone acetylation and methylation. 

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