A Universal Theme
The complexes formed by activators, coactivators and the basal machinery appear to be human equivalents of sigma factors; they, too, draw RNA polymerase to specific genes at specific rates. In a way, the complexes can be viewed as sigma factors that have been elaborated into many subunits. Gratifyingly, recent evidence from our group and others suggests we have uncovered a universal mode of gene regulation in eukaryotes. Those studies confirm that coactivators also exist in yeast and that factor D consists of multiple subunits in fungi as well as in humans.
As satisfying as these results are, they do not fully explain how binding of activators to enhancers and to coactivators influences the rate at which RNA polymerase transcribes genes in living cells. It may be that linkage of activators to enhancers causes DNA to bend in a way that brings the enhancers closer to one another and to the core promoter. This arrangement may help activators (alone or in concert with one another) to dock with coactivators and position factor D on the promoter. This step, in turn, would facilitate assembly of the complete basal complex. Formation of this complex may distort the underlying DNA in a way that enables RNA polymerase to begin its journey along the coding region.
Researchers know less about the functioning of repressors. Nevertheless, many of us think repressors may also bind to coactivators at times. This binding could inhibit transcription by preventing activators from attaching to their usual sites on coactivators. Other times repressors might bypass the basal machinery, blocking transcription by preventing activators from connecting with enhancers.
Although there are gaps in our knowledge, we can now begin to sketch out an explanation as to why different cells make different mixtures of proteins during embryonic development and in mature organisms. A gene will be transcribed at a measurable rate only if the various activators it needs are present and can successfully overcome the inhibitory effects of repressors. Cells vary in the proteins they make because they contain distinct batteries of activators and repressors. Of course, this scenario begs the question of how cells decide which transcription factors to produce in the first place, but progress is being made on that front as well.
Therapies of Tomorrow How might investigators use our newly acquired knowledge of gene regulation to develop drugs for combating life-threatening diseases involving excessive or inadequate transcription of a gene? In theory, blocking selected activators from attaching to enhancers or coactivators should depress unwanted transcription, and stabilizing the transcription machinery on a gene should counteract undesirably weak transcription.
Blockade could be achieved by fitting a molecular "plug" into an activator, thereby preventing its interaction with a coactivator, or by enticing an activator to attach to a decoy that resembles a coactivator. Stabilization of a complex might be achieved by deploying molecules that would strengthen the interaction between activators and DNA or between activators and coactivators. Such approaches are remote today, but it is exciting to consider a sampling of the applications that might eventually be possible.
Take, for example, the human immunode ficiency virus (HIV), which causes AIDS. To reproduce itself in human cells, HIV needs the viral transcription factor TAT to enhance transcription of HIV genes. If TAT could be inhibited by some agent that recognized TAT but ignored human transcription factors, replication of the virus might be halted without affecting production of proteins needed by the patient.