Transcription activator Methylation

Histone methylation by methyltransferases is another vddely described modification that also plays an important role in regulation of transcriptional activity. Methylation can occur either on arginine or on lysine residues in the N-termini of histones and therefore this group of enzymes can be separated into protein arginine methyltransferases (PRMTs) and lysine methyltransferases (KMTs). 

The transcriptional activity of NRs is also modulated by various posttranslational modifications of the receptors themselves or of their coregulatory proteins. Phosphorylation, as well as several other types of modification, such as acetylation, SUMOylation, ubiquitinylation, and methylation, has been reported to modulate the functions of NRs, potentially constituting an important cellular integration mechanism. In addition to the modifications of the receptors themselves, such modifications have been reported for their coactivators and corepressors. Therefore, these different modes of regulation reveal an unexpected complexity of the dynamics of NR-mediated transcription. 

The core unit of the chromatin, the nucleosome, consists of histones arranged as an octamer consisting of a (H3/ H4)2-tetramer complexed with two histone H2A/H2B dimers. Accessibility to DNA-binding proteins (for replication, repair, or transcription) is achieved by posttranslational modifications of the amino-termini of the histones, the histone tails phosphorylation, acetylation, methylation, ubiquitination, and sumoyla-tion. Especially acetylation of histone tails has been linked to transcriptional activation, leading to weakened interaction of the core complexes with DNA and subsequently to decondensation of chromatin. In contrast, deacetylation leads to transcriptional repression. As mentioned above, transcriptional coactivators either possess HAT activity or recruit HATs. HDACs in turn act as corepressors. 

Metivier, R, R Gallais, C Tiffoche et al. 2008. Cyclical DNA methylation of a transcriptionally active promoter. Nature 452 45-50. 

Apart from telomeres, G-quadruplexes are also present in the upstream promoter regions of certain oncogenes. G-quadruplex targeted molecules may interact at these sites as well. In fact, the cationic prophyrin, TMPyP4 and the core modified expanded prophyrin analogue 5,10,15,20-[tetra(N-methyl-3-pyridyl)]-26,28-diselenasapphyrin chloride (Se2SAP) have been found to cause repression of transcriptional activation of c-MYC in cells by G-quadruplex stabilization (Seenisamy et al, 2005). 

We have discussed phosphorylation of histone H3, which has been studied in many organisms. Phosphorylation of histone H3 (SIO) has two opposite main functions. One is necessary to initiate chromosome condensation during mitosis and meiosis, while the other is transcriptional activation. Current evidence shows that a combination of phosphorylation of H3 (SIO) and methylation of H3 (K9) or acetylation H3 (K9, K14) play important roles in these phenomena including cell cycle related chromosome dynamics and transcriptional activation. These results suggest that a combination of different histone modifications excute different biological outcomes. 

Allfrey VG, Faulkner R, Mirsky AE (1964) Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc Natl Acad Sci USA 51 786-794 An W, Kim J, Roeder RG (2004) Ordered cooperative functions of PRMYl, p300, and CARMl in transcriptional activation by p53. Cell 117 1-20... 

Saito A, Yamashita T, Mariko Y, Nosaka Y, Tsuchiya K, Ando T, Suzuki T, Tsurao T, Nakanishi O (1999) A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. Proc Natl Acad Sci USA 96(8) 4592-4597 Schneider R, Bannister AJ, Myers FA, Thorne AW, Crane-Robinson C, Kouzarides T (2004) Histone H3 lysine 4 methylation patterns in higher eukaryotic genes. Nature 6 73-77 Schwartz BE, Ahmad K (2005) Transcriptional activation triggers deposition and removal of the histone variant H3.3. Genes Dev 19 804-814... 

One possible function for H3.3 and some of the other replacement variants is to maintain the integrity of chromatin structure by replacing histones that are damaged or lost during normal cellular metabolism. Ahmad and Henikoff [104] suggested that replication independent incorporation of H3.3 could provide a mechanism to switch patterns of histone modification by removing H3 molecules that may be irreversibly modified by methylation. They also suggested that H3.3 could serve as a mark of transcriptionally active chromatin. One complication for... 

As described above, histones are much more than passive structural players within chromatin. Dynamic post-translational modifications of these proteins confer specialized chemical proprieties to chromatin of both informational and structural nature with important functional implications. The highly conserved sites for acetylation, methylation, phosphorylation, ADP-ribosylation, and ubiquitination events on histone tails appear to orchestrate functional activities that range from transcriptional activation and repression to DNA repair and recombination. 

In a supplementary pathway, links between histone H3 Lys4 methylation and the upregulation of RNA synthesis have also been made. This discrete modification colocalizes with acetylated histone residues and is enriched in the transcriptionally active macronucleus of Tetrahymena [194]. Histone methylation at H3 Lys4 has been recently attributed to the novel HMT SET9, which contains the conserved SET catalytic domain, and noticeably lacks the juxtaposed pre- and post-SET... 

Fig. 4. Domain structure of mammalian DNA methyltransferases. (a) The domain structure of the known DNA methyltransferases, depicting the conserved catalytic domain (dark box) and other identified domains. Conserved aminoacid motifs in the catalytic domain are shown in lighter shade of gray. (b) Schematic representation of the reported protein-protein interactions of Dnmtl with a number of regulatory proteins interactions that modulate Dnmtl methyitransferase activity (darker rectangles) or mediate methylation-independent transcriptional repression mechanisms (lighter rectangles). When Dnmtl represses transcription through its enzymatic activity, it has been described to interact with some proteins PCNA [37] and an oncogenic transcription factor PML-RAR [25]. Note that in the case of the PML-RAR transcription factor, histone deacetylase 1 (HDACl) is also bound to the complex. When Dnmtl represses transcription via methylation-independent pathways, it binds to HDACs either directly [34] or indirectly through other proteins the corepressor DMAPl [33], the retinoblastoma protein, and a gene-specific transcription factor [31].

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