such as "Introduction", "Conclusion"..etc
Differentiation of tissues results from the expression of asubset of tissue-specific genes that are driven by their promoter.These promoters consist of generalized basal transcription machinery,general activators, plus more specific activators that bindto cis elements in the DNA (Hahn, 1998). Coactivators, residingwithin protein complexes, bind to the DNA-binding activatorsby protein–protein interaction partly to relay biologicalsignals to the basal transcription machinery (Bjorklund et al.,1999). A common feature of coactivator complexes is the histoneacetyltransferase (HAT) activity (Struhl, 1998) that acetylatesneighboring nucleosomes, facilitating the opening of the DNAto allow access of RNA polymerase II holoenzyme.
This activation of genes can be reversed in some cases by corepressorcomplexes that must replace activating complexes. These corepressorcomplexes contain enzymes that remove acetate groups from histones(Glass and Rosenfeld, 2000) to close the DNA template. Thesehistone deacetylases (HDACs) are brought to the DNA within thesecomplexes that are nucleated by a number of corepressors: N-CoR,SMRT, and mSin3A/B (Glass and Rosenfeld, 2000). It is the exchangeof the activation complex with a repression complex that resultsin a dramatic change in gene expression. Nevertheless, repressionof several genes cannot be accounted for entirely by HDAC activity(Perissi and Rosenfeld, 2005). Furthermore, the compositionof the corepressor enzyme complexes appears to be quite variable(Ishizuka and Lazar, 2003) which allows for a wide range ofpromoters to be regulated while maintaining the required specificity.Generally, though, the chromatin structure must be enzymaticallymodified by the HDACs to contribute to the repression of promoteractivity.
Metazoans need more stringent gene repression. One way to accomplishthis stringency is through the synergy arising from the cooperationof more than one posttranslational modification acting at differentsites. Recently, our laboratory added the O-GlcNAc posttranslationalmodification to the HDACs in the cooperative repression of transcription(Yang et al., 2002). The corepressor mSin3A recruits both HDACand O-GlcNAc transferase (OGT), the enzyme responsible for thislatter modification (Roos and Hanover, 2000), to repressed genes.The O-GlcNAc posttranslational modification occurs in both multicellularplants (Hartweck et al., 2002) and animals (O’Donnell,2002). In higher animals, O-GlcNAcylation of the ubiquitousSp1 transcriptional activator makes this GC-binding factor incapableof activating transcription (Roos et al., 1997; Yang et al.,2001), even though it can still bind to DNA (Jackson and Tjian,1988; Sekinger and Gross, 2001). But even in the absence ofa GC box, OGT targeted to DNA can repress basal transcription,perhaps by modifying the tail of RNA polymerase II (Comer andHart, 2001). Through these effects, and effects on proteasomeactivity, signal transduction, and secretion, O-GlcNAc can regulatedevelopment and other vital cellular processes (Gao et al.,2001; Wells et al., 2001; Yang et al., 2001; Zhang et al., 2003;Liu et al., 2004). By cooperating with the HDACs that changechromatin structure, the physical coassociation of OGT allowsit to modify the transcriptional apparatus. By turning the transcriptionoff, O-GlcNAcylation can add to gene repression through an HDAC-independentmechanism. The corepressor mSin3A, by recruiting both HDAC andOGT through defined domains only to the repressed genes, ensuresthe specificity of both these modifiers. Furthermore, the stringentrepression of gene expression occurs through the synergy ofthese repressive modifications acting in concert.
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