The Enhanceosome and Minireview Transcriptional Synergy

on the arrangement of activator recognition sites and the precise complement of bound activators, which together generate a network of protein–protein and pro-tein–DNA interactions unique to a given enhancer. The free energy of enhanceosome formation is fine-tuned to Los Angeles, California 90095-1737 the concentration of the relevant activators in a cell and their ability to engage in combinatorial interactions; subthreshold concentrations (see Figure 1), the absence Development of a complex eukaryote requires the differ-of key activators, or altered positioning on the DNA pro-ential transcription of over 50,000 genes in precise spa-hibit cooperative binding. As illustrated in Figure 2, the tial and temporal patterns. One of the key problems enhanceosome displays two layers of " stereo-specific-in the gene expression field is understanding how an ity " necessary for gene activation. In one, the contextual organism can achieve such diversity, while maintaining activator–activator interactions promote cooperative cell specificity and responding dynamically to its envi-assembly of the enhanceosome on naked DNA or chro-ronment. One solution is to employ a limited repertoire matin templates, an issue addressed by several previous of activators to minimize the complexity necessary to studies from the Maniatis and Grosschedl labs (Giese et link related signaling pathways and to integrate diverse al. regulatory cues. The current view is that the cell accom-1997) and a recent study by Jones and colleagues (May-plishes this by employing the principles of cooperativity all et al., 1997). In the other, the enhanceosome displays and transcriptional synergy (Figure 1), where small coma specific activation surface that is chemically and binations of ubiquitous, signal-and tissue-specific acti-spatially complementary to " target " surfaces on coacti-vators can be used to execute an exponentially larger vators and the basal pol II transcriptional machinery, number of regulatory decisions. Thus, an RNA polymer-ase II (pol II) enhancer responds to signals by organizing unique combinations of activators in a tightly clustered pattern that promotes their interaction and cooperative binding to DNA. The pol II transcriptional machinery, in turn, is designed to respond in a greater-than-additive or synergistic fashion only to multiple activators. Previous studies from the Maniatis and Grosschedl laboratories on the IFN␤ and TCR␣ gene enhancers, respectively, provided important biochemical details of how enhancer organization and cooperativity functioned to assemble activators into a nucleoprotein complex called the " enhanceosome. " A key unanswered question was " how does the enhanceosome stimulate synergistic transcription and is the precise stereo-specific arrangement of activation domains …