Abstract
In mammals, flies, and worms, sex is determined by distinctive regulatory mechanisms that cause males (XO or XY) and females (XX) to differ in their dose of X chromosomes. In each species, an essential X chromosome-wide process called dosage compensation ensures that somatic cells of either sex express equal levels of X-linked gene products. The strategies used to achieve dosage compensation are diverse, but in all cases, specialized complexes are targeted specifically to the X chromosome(s) of only one sex to regulate transcript levels. In C. elegans, this sex-specific targeting of the dosage compensation complex (DCC) is controlled by the same developmental signal that establishes sex, the ratio of X chromosomes to sets of autosomes (X:A signal). Molecular components of this chromosome counting process have been defined. Following a common step of regulation, sex determination and dosage compensation are controlled by distinct genetic pathways. C. elegans dosage compensation is implemented by a protein complex that binds both X chromosomes of hermaphrodites to reduce transcript levels by one-half. The dosage compensation complex resembles the conserved 13S condensin complex required for both mitotic and meiotic chromosome resolution and condensation, implying the recruitment of ancient proteins to the new task of regulating gene expression. Within each C. elegans somatic cell, one of the DCC components also participates in the separate mitotic/meiotic condensin complex. Other DCC components play pivotal roles in regulating the number and distribution of crossovers during meiosis. The strategy by which C. elegans X chromosomes attract the condensin-like DCC is known. Small, well-dispersed X-recognition elements act as entry sites to recruit the dosage compensation complex and to nucleate spreading of the complex to X regions that lack recruitment sites. In this manner, a repressed chromatin state is spread in cis over short or long distances, thus establishing the global, epigenetic regulation of X chromosomes that is maintained throughout the lifetime of hermaphrodites.
Highlights
In numerous organisms, sex is determined by a chromosome counting mechanism that distinguishes one sex chromosome from two
The strategies for dosage compensation are diverse in different organisms (Figure 1), but in all known cases, specialized dosage compensation complexes are targeted exclusively to the X chromosome(s) of one sex to modulate gene expression in only that sex
What is the composition of the machinery that implements dosage compensation? Second, what are the sex-specific factors that activate the dosage compensation machinery in only one sex? Third, what are the cis-acting recruitment sites that target X chromosomes for regulation by the dosage compensation complex? Fourth, how is gene expression coordinately controlled along an entire X chromosome? Fifth, what is the molecular mechanism for fine-tuning X-linked gene expression by only two-fold? These basic questions have been addressed in C. elegans, using integrated genetic, biochemical, and cell biological approaches to dissect this regulatory process
Summary
Sex is determined by a chromosome counting mechanism that distinguishes one sex chromosome from two. Sex can be specified by the presence of a particular sex chromosome, such as the Y chromosome of mammals: XY embryos are males, and XX embryos females (Gubbay et al, 1990; Koopman et al, 1991; Sinclair et al, 1990) These sex-determining mechanisms cause the two sexes to differ in their dose of X chromosomes, yet both sexes require equivalent levels of X-chromosome gene products. The strategies for dosage compensation are diverse in different organisms (Figure 1), but in all known cases, specialized dosage compensation complexes are targeted exclusively to the X chromosome(s) of one sex to modulate gene expression in only that sex This selective recruitment of the dosage compensation machinery establishes the epigenetic regulation of X chromosomes that is maintained throughout the lifetime of the animal. What is the composition of the machinery that implements dosage compensation? Second, what are the sex-specific factors that activate the dosage compensation machinery in only one sex? Third, what are the cis-acting recruitment sites that target X chromosomes for regulation by the dosage compensation complex? Fourth, how is gene expression coordinately controlled along an entire X chromosome? Fifth, what is the molecular mechanism for fine-tuning X-linked gene expression by only two-fold? These basic questions have been addressed in C. elegans, using integrated genetic, biochemical, and cell biological approaches to dissect this regulatory process
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