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Transcription in multicellular organisms, whether plant or animal,<sup></sup>is controlled in precise spatial and temporal patterns, resulting<sup></sup>in proper differentiation, development, and homeostasis. Although,<sup></sup>expression of certain genes in differentiated tissue is forbidden,<sup></sup>others can be activated by environmental or hormonal signals.<sup></sup>One way to accomplish this homeostatic control rapidly and thoroughly<sup></sup>is through cooperative posttranslational modifications of existing<sup></sup>proteins.<sup></sup><p> Differentiation of tissues results from the expression of a<sup></sup>subset of tissue-specific genes that are driven by their promoter.<sup></sup>These promoters consist of generalized basal transcription machinery,<sup></sup>general activators, plus more specific activators that bind<sup></sup>to <em>cis</em> elements in the DNA (Hahn, 1998<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#HAHN-1998"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>). Coactivators, residing<sup></sup>within protein complexes, bind to the DNA-binding activators<sup></sup>by protein–protein interaction partly to relay biological<sup></sup>signals to the basal transcription machinery (Bjorklund <em>et al</em>.,<sup></sup>1999<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#BJORKLUND-ET-AL-1999"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>). A common feature of coactivator complexes is the histone<sup></sup>acetyltransferase (HAT) activity (Struhl, 1998<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#STRUHL-1998"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>) that acetylates<sup></sup>neighboring nucleosomes, facilitating the opening of the DNA<sup></sup>to allow access of RNA polymerase II holoenzyme.<sup></sup></p> <p> This activation of genes can be reversed in some cases by corepressor<sup></sup>complexes that must replace activating complexes. These corepressor<sup></sup>complexes contain enzymes that remove acetate groups from histones<sup></sup>(Glass and Rosenfeld, 2000<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#GLASS-AND-ROSENFELD-2000"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>) to close the DNA template. These<sup></sup>histone deacetylases (HDACs) are brought to the DNA within these<sup></sup>complexes that are nucleated by a number of corepressors: N-CoR,<sup></sup>SMRT, and mSin3A/B (Glass and Rosenfeld, 2000<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#GLASS-AND-ROSENFELD-2000"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>). It is the exchange<sup></sup>of the activation complex with a repression complex that results<sup></sup>in a dramatic change in gene expression. Nevertheless, repression<sup></sup>of several genes cannot be accounted for entirely by HDAC activity<sup></sup>(Perissi and Rosenfeld, 2005<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#PERISSI-AND-ROSENFELD-2005"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>). Furthermore, the composition<sup></sup>of the corepressor enzyme complexes appears to be quite variable<sup></sup>(Ishizuka and Lazar, 2003<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#ISHIZUKA-AND-LAZAR-2003"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>) which allows for a wide range of<sup></sup>promoters to be regulated while maintaining the required specificity.<sup></sup>Generally, though, the chromatin structure must be enzymatically<sup></sup>modified by the HDACs to contribute to the repression of promoter<sup></sup>activity.<sup></sup></p> <p> Metazoans need more stringent gene repression. One way to accomplish<sup></sup>this stringency is through the synergy arising from the cooperation<sup></sup>of more than one posttranslational modification acting at different<sup></sup>sites. Recently, our laboratory added the <em>O</em>-GlcNAc posttranslational<sup></sup>modification to the HDACs in the cooperative repression of transcription<sup></sup>(Yang <em>et al</em>., 2002<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#YANG-ET-AL-2002"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>). The corepressor mSin3A recruits both HDAC<sup></sup>and <em>O</em>-GlcNAc transferase (OGT), the enzyme responsible for this<sup></sup>latter modification (Roos and Hanover, 2000<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#ROOS-AND-HANOVER-2000"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>), to repressed genes.<sup></sup>The <em>O</em>-GlcNAc posttranslational modification occurs in both multicellular<sup></sup>plants (Hartweck <em>et al</em>., 2002<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#HARTWECK-ET-AL-2002"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>) and animals (O’Donnell,<sup></sup>2002<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#ORDONNELL-2002"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>). In higher animals, <em>O</em>-GlcNAcylation of the ubiquitous<sup></sup>Sp1 transcriptional activator makes this GC-binding factor incapable<sup></sup>of activating transcription (Roos <em>et al</em>., 1997<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#ROOS-ET-AL-1997"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>; Yang <em>et al</em>.,<sup></sup>2001<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#YANG-ET-AL-2001"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>), even though it can still bind to DNA (Jackson and Tjian,<sup></sup>1988<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#JACKSON-AND-TJIAN-1988"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>; Sekinger and Gross, 2001<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#SEKINGER-AND-GROSS-2001"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>). But even in the absence of<sup></sup>a GC box, OGT targeted to DNA can repress basal transcription,<sup></sup>perhaps by modifying the tail of RNA polymerase II (Comer and<sup></sup>Hart, 2001<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#COMER-AND-HART-2001"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>). Through these effects, and effects on proteasome<sup></sup>activity, signal transduction, and secretion, <em>O</em>-GlcNAc can regulate<sup></sup>development and other vital cellular processes (Gao <em>et al</em>.,<sup></sup>2001<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#GAO-ET-AL-2001"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>; Wells <em>et al</em>., 2001<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#WELLS-ET-AL-2001"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>; Yang <em>et al</em>., 2001<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#YANG-ET-AL-2001"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>; Zhang <em>et al</em>., 2003<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#ZHANG-ET-AL-2003"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>;<sup></sup>Liu <em>et al</em>., 2004<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#LIU-ET-AL-2004"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>). By cooperating with the HDACs that change<sup></sup>chromatin structure, the physical coassociation of OGT allows<sup></sup>it to modify the transcriptional apparatus. By turning the transcription<sup></sup>off, <em>O</em>-GlcNAcylation can add to gene repression through an HDAC-independent<sup></sup>mechanism. The corepressor mSin3A, by recruiting both HDAC and<sup></sup>OGT through defined domains only to the repressed genes, ensures<sup></sup>the specificity of both these modifiers. Furthermore, the stringent<sup></sup>repression of gene expression occurs through the synergy of<sup></sup>these repressive modifications acting in concert.<sup></sup></p> A bifunctional enzyme, formerly called Mgea5/<em>O</em>-GlcNAcase (Gao<sup></sup><em>et al</em>., 2001<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#GAO-ET-AL-2001"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>), is the only protein known to remove the <em>O</em>-GlcNAc<sup></sup>modification with its N-terminal <em>O</em>-GlcNAcase domain (Clifford<sup></sup>Toleman, personal communication). In addition, this protein,<sup></sup>like many others, has a HAT domain (Toleman <em>et al</em>., 2004<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#TOLEMAN-ET-AL-2004"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>) and<sup></sup>has been accordingly termed the nuclear/cytoplasmic <em>O</em>-GlcNAcase<sup></sup>and acetyl transferase (NCOAT). Because NCOAT has these two<sup></sup>domains, one that reverses the OGT modification and the other<sup></sup>that reverses the HDAC modification, NCOAT fulfils the requirement<sup></sup>of reversibility of gene repression. To test this idea, we extended<sup></sup>our prior studies on estrogen signals in the nucleus (Yang <em>et<sup></sup>al</em>., 2002<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#YANG-ET-AL-2002"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>). In the course of our studies, we learned that NCOAT<sup></sup>associates with its opposite, OGT, very tightly. This unusual<sup></sup>association of opposite enzymes also gives a means by which<sup></sup>NCOAT can be as gene specific as OGT, and, by residing with<sup></sup>OGT in the repression complex, it is strategically placed to<sup></sup>reverse both repressive modifications rapidly: <em>O</em>-GlcNAcylation<sup></sup>and deacetylation. However, this association of opposing enzymes<sup></sup>is a biological conundrum, because it provides the possibility<sup></sup>of a futile cycle. However, in this article, we show that such<sup></sup>a cycle of <em>O</em>-GlcNAcylation does not occur probably because both<sup></sup>NCOAT activities are regulated (Toleman <em>et al</em>., 2004<a href="http://glycob.oxfordjournals.org/cgi/content/full/16/6/551#TOLEMAN-ET-AL-2004"><img src="http://glycob.oxfordjournals.org/icons/fig-down.gif" alt="Go"></a>), and its<sup></sup>unique <em>O</em>-GlcNAcase activity is converse to that of its association<sup></sup>partner, OGT.
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