Transcriptional regulation and the role of diverse coactivators in animal cells
914 R.G. Roeder / FEBS Letters 579 (2005) 909–915 (M. Guermah and R.G. Roeder, unpublished observations). Studies of the nature, functional specificity (for different activators and different histone-modifying cofactors), and mechanism of action of this factor(s) are underway. The in vitro studies of transcription activation from DNA versus chromatin templates have led to a general model [27,35,39] involving activator-dependent recruitment and function of chromatin remodeling/modifying factors followed by activator-dependent formation and function of the preinitiation complex through a mechanism(s) involving additional cofactors such as Mediator (Fig. 2). A major question concerns the mechanism(s) involved in transitions from activator-dependent chromatin remodeling/modification steps to activator-dependent PIC formation/function, especially in cases (e.g., nuclear receptors) where chromatin remodelers/ modifiers and Mediator interact with identical or overlapping surfaces (activation domains) in the activators [reviewed in 39]. The transitions could be a simple matter of equilibrium reactions, with both types of cofactors interacting with promoter bound activators within chromatin but with Mediator interactions being unproductive until chromatin remodeling/ modifying factor interactions have resulted in chromatin structural changes that facilitate subsequent Mediator interaction and PIC formation through cooperative stabilizing interactions . Another appealing possibility is the involvement of additional cofactors that interact physically and functionally both with chromatin remodeling/modifying cofactors and with Mediator or PIC components. Of significance in this regard is our recent demonstration that PGC-1a, an inducible coactivator that interacts with nuclear receptors [reviewed in 71], interacts with and stimulates the function of both p300 and Mediator in nuclear receptor (PPARc)-dependent transcription  (Fig. 4). The PGC-1a-enhanced Mediator function is evident on DNA templates in the absence of the p300 binding site in the N-terminal region of PGC-1a. However, the effect of PGC-1a on p300-dependent transcription from a chromatin template requires both the N-terminal p300 interaction site and the C-terminal Mediator interaction site on PGC-1a, thus suggesting that the effect of PGC-1a on p300 may be linked to the effect on TRAP/Mediator. Along with the presence of multiple interaction sites between the various factors and largely non-overlapping interaction sites for PPARc, p300 and TRAP220 on PGC-1a, this suggests a model (Fig. 4) wherein PGC-1a may facilitate the transition (including cofactor exchange) between a chromatin remodeling step involving ligand-dependent binding of p300 to PPARc and a later transcription activation step involving ligand-dependent binding of TRAP/Mediator to PPARc. Itis envisioned that alternative dynamic interactions of the various components may both stabilize and enhance the function of the different complexes and, perhaps through a transient intermediate complex containing all components, facilitate the transition between them. Of significant interest is whether PGC-1a will serve as a prototype for other cofactors acting in conjunction with other transcriptional activators. Because gene activation in the cell may involve a requisite sequence of events (e.g., chromatin modifications prior to PIC formation), the use of biochemically defined systems in which partial reactions can be studied will be essential for identification and/or for elaborating the mechanism(s) of action of such cofactors. 4. Conclusions and perspectives Beginning with the discovery of the three nuclear RNA polymerases 35 years ago, biochemical (and more recently genetic) studies have identified a remarkably complex general transcription machinery and an equally complex array of coregulatory factors that facilitate functional interactions of DNA binding regulatory factors (numbering several thousand) with this machinery on corresponding target genes. This complex transcriptional apparatus appears to have evolved to facilitate the proper execution and regulation of the diverse and finely tuned gene activation pathways that are critical for normal development, cell differentiation and homeostasis. This complex apparatus allows (i) global control mechanisms for the major classes of RNA, (ii) mechanisms to activate or repress genes packaged within natural chromatin structures, (iii) multiple targets for the cooperative functions of combinations of DNA-binding regulatory factors, (iv) mechanisms for the integration of multiple signaling pathways and (v) a basis for alternative or redundant gene activation and repression pathways that may contribute to biological robustness . 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