Getting the right dose of repression.

In recent years, it has become apparent that eukaryotic transcriptional repression mechanisms are remarkably varied in their modes of action and effects. Repression can be established by proteins that act over a short range, or at a long distance (Mannervik et al. 1999). Some mechanisms of repression are readily reversible, but others establish a heritable state of long-term silencing (Moazed 2001). Many transcriptional repressors alter chromatin structure through histone deacetylation or methylation, and thereby affect nucleosome positioning and accessibility of the DNA to positively acting factors (Kornberg and Lorch 1999; Zhang and Reinberg 2001). Multiple steps in transcriptional initiation are also sensitive to obstruction by repressors (Maldonado et al. 1999), and individual repressors such as Ssn6–Tup1 target both chromatin and the RNA Pol II complex (Smith and Johnson 2000). The Caenorhabditis elegans germ line transcriptional repressor PIE-1 is a predicted RNAbinding protein that appears to act after initiation (Batchelder et al. 1999; Tenenhaus et al. 2001). This array of mechanisms makes it possible to inhibit genes in an extraordinarily wide variety of biological contexts. We understand less about how repression might be tailored to achieve particular levels of inhibition. This is a seemingly simple matter if the goal is for a gene to be in an “off” state, although whether the repressed state is to be rapidly reversible could add a further level of complexity. But what if having an on/off switch is not enough, and instead a partial suppression of transcription is required, to attain a particular level of expression? Furthermore, what if the biological program in which this partial repression is needed also requires that other genes be inhibited more completely? Can the same or overlapping repression mechanisms be customized to have different effects at different loci, a scheme that would provide the simplest solution to the problem? Can these same mechanisms be used both to inhibit individual genes and establish a global repression over a large region? Precisely the above situation is presented during establishment of the hermaphrodite fate in C. elegans. In these nematodes, whether an individual becomes a hermaphrodite (XX) or male (XO) is determined by the number of sex chromosomes present (Meyer 2000). In hermaphrodites, transcription of nearly all genes on both X chromosomes must be reduced by half, to bring their expression in line with levels that arise from a single X chromosome in males. This process is called dosage compensation, a term that refers to the various mechanisms by which species alter expression of sex chromosome genes in one sex, to compensate for the difference in chromosome number between the two sexes (Marin et al. 2000). Dosage compensation mechanisms are considerably diverse: for example, in Drosophila, transcription of X chromosome genes is doubled in males, but in mammals one of the two X chromosomes is inactivated in females. In C. elegans, in addition to a twofold global reduction in X chromosome transcription, the hermaphrodite fate also depends on specific repression of the autosomal male sex-determination gene her-1 (Meyer 2000). In contrast to dosage compensation, this specific repression of her-1 involves a more than 20-fold reduction in transcription. Evidence that these two distinct repression processes require some of the same proteins (Meyer 2000), has suggested that they may share some targeting or effector mechanisms. In a recent study, the Meyer laboratory has shown that both her-1 repression and dosage compensation are mediated through direct assembly of the same complex of proteins, referred to as the dosage compensation complex (Fig. 1; Chu et al. 2002). How can this protein complex establish such dramatically variant levels of specific and chromosome-wide repression? The dosage compensation complex also represses to different degrees when it is bound to different individual her-1 DNA regulatory elements. Surprisingly, these repression levels do not appear to correlate with the affinity of DNA binding, suggesting that the dosage compensation complex can have significantly different effects within when it is recruited within different contexts. An important strength of these experiments is that they were performed in vivo, and have thereby provided a window into what is actually happening at these target loci. They have defined a fascinating question for further study: How does the milieu in which the dosage compensation complex is recruited influence its function?