Targeting X chromosomes for repression

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Dosage compensation is a chromosome-wide regulatory process that balances X-chromosome gene expression between males and females that have different complements. Recent advances have clarified the molecular nature of the Caenorhabditis elegans sex-determination signal, which tallies X-chromosome number relative to the ploidy and controls both the choice of sexual fate and the process of dosage compensation. Dissecting the sex signal has revealed molecular mechanisms by which small quantitative differences in intracellular signals are translated into dramatically different developmental fates. Recent experiments have also revealed fundamental principles by which C. elegans dosage compensation proteins recognize and bind X chromosomes of XX embryos to reduce gene expression. Dosage compensation proteins function not only in a condensin complex specialized for regulating X-chromosome gene expression, but also in distinct condensin complexes that control other chromosome-wide processes: chromosome segregation and meiotic crossover recombination. The reshuffling of interchangeable molecular parts creates independent machines with similar architecture but distinct biological functions.

Introduction

Organisms that determine sex using chromosome-based mechanisms (e.g. XX female and XY or XO male), have evolved the essential, chromosome-wide regulatory process called dosage compensation to balance sex-chromosome gene expression between the sexes [1]. Strategies for dosage compensation differ, but invariably a regulatory complex is targeted to the sex chromosome of one sex to modulate transcript levels across the entire chromosome. Dosage compensation is exemplary for dissecting the coordinate regulation of gene expression over vast distances and the role of chromosome structure in controlling gene expression.

Mammals randomly inactivate one of the two female X chromosomes using noncoding RNAs that recruit the Polycomb complex [2, 3]. Transient pairing of X chromosomes through the X-inactivation center heralds the onset of inactivation and helps specify the X to become inactivated [4, 5]. A repressive nuclear compartment reliant on noncoding RNAs recruits the X genes to be silenced [6]. In contrast, flies increase expression of the single male X chromosome through a complex containing noncoding RNAs and MSL (Male-Specific Lethal) proteins that binds the male X and acetylates histones [7]. Nematodes reduce expression of both X chromosomes in hermaphrodites by half through a dosage compensation complex (DCC) that binds the two X chromosomes [8]. The DCC resembles condensin, a protein complex conserved from yeast to humans to promote the compaction, resolution, and segregation of chromosomes during mitosis and meiosis [9, 10•, 11, 12]. In all three examples, selective recruitment of the dosage compensation machinery establishes the epigenetic regulation of X chromosomes that is maintained throughout the lifetime of the animal.

Fundamental issues relevant to all forms of dosage compensation include the nature of the regulatory pathway and sex-specific factors that activate dosage compensation in only one sex, the composition of the dosage compensation machinery, the cis-acting sites that selectively target the X chromosome for regulation, and the mechanism of fine tuning gene expression. This review focuses on Caenorhabditis elegans dosage compensation, with brief comparisons to Drosophila melanogaster. Emphasis is placed on recent advances in understanding, firstly, the C. elegans regulatory hierarchy that controls dosage compensation, including the primary sex-determination signal, secondly, fundamental principles by which the DCC recognizes and binds X chromosomes, and thirdly, the roles of dosage compensation proteins in controlling other chromosome-wide processes through association with distinct condensin complexes: crossover recombination during meiosis and chromosome segregation during mitosis and meiosis.

Section snippets

X:A signal: X and autosomal signal elements oppose each other to determine C. elegans sex

C. elegans determines sex by tallying X-chromosome number relative to the ploidy, the number of sets of autosomes (X:A signal) (Figure 1a) [13, 14]. Ratios of 1X:2A and 2X:3A elicit male fate, while 2X:2A and 3X:4A elicit hermaphrodite fate. Not only does the X:A signal dictate sexual fate, but also it establishes the level of X-linked gene expression by controlling the process of dosage compensation [15, 16]. Dissecting the sex-determination signal in C. elegans has revealed molecular

The dosage compensation complex

Repression of xol-1 in XX embryos permits the novel, XX-specific protein SDC-2 (sex determination and dosage compensation) to be active and thereby induce hermaphrodite sexual development and initiate dosage compensation (Figure 2a) [36, 37]. SDC-2 acts with the zinc-finger proteins SDC-1 and SDC-3 to induce hermaphrodite development by repressing her-1, a sex-determination gene that elicits male development [37, 38, 39]. SDC proteins inactivate her-1 directly by binding to three sites in the

Targeting the DCC to X chromosomes: cis-acting sites

The combination of the genome-wide approach to identify DCC binding sites without regard to recruitment ability and the functional approach in vivo to assess DCC recruitment to sites detached from X showed the DCC binds to discrete, dispersed sites on X that partition into two classes (Figure 2, Figure 3) [53••]. rex sites (recruitment elements on X) recruit the DCC in an autonomous, DNA-sequence-dependent manner using a 12 base pair MEX consensus motif that is enriched on X compared to

DCC loading onto X

Discovery of autonomous (rex) and dependent (dox) DCC binding sites suggests a model by which the DCC loads onto X chromosomes. The DCC binds to rex sites, which recruit additional complexes to bind along X [53••]. This model is supported and refined by two additional sets of experiments that address the relationship between DCC binding at rex and dox sites. First, ChIP-chip analysis of DCC binding in mutants lacking any one of the recruitment proteins SDC-2, SDC-3, or DPY-30 showed that

Comparison of X-chromosome recognition and dosage compensation complex binding in flies and nematodes

Although the dosage compensation complexes of flies and nematodes are evolutionarily unrelated and regulate X chromosomes in opposite ways, similar principles appear to govern the X-chromosome targeting and binding of the two complexes. In flies, dosage compensation is achieved by the MSL complex, which binds to the single X chromosome of males to increase transcript levels [7]. As in worms, about 150 special chromatin entry sites recruit the MSL complex in a DNA-sequence-dependent manner using

The C. elegans DCC acts at a distance to repress genes on X

The mechanism of dosage compensation in C. elegans was explored by correlating the locations of DCC binding sites with the genes responsive to dosage compensation [53••]. Several striking conclusions emerged. First, the DCC neither compensates all X genes, nor does it always achieve a precise twofold repression when it does. Second, although the DCC binds preferentially to more highly expressed genes on X, it can compensate X genes of all expression levels. Third and most unexpected, DCC

Autosomal gene expression is affected by the DCC

DCC disruption causes opposite effects on X and autosomal genes: X genes have increased expression, and one-fourth of autosomal genes have reduced expression [53••]. The DCC thus affects expression throughout the genome. The DCC binding sites on autosomes correlate infrequently with genes affected by dosage compensation mutations. The effect of DCC disruption on autosomal gene expression cannot simply be explained by an indirect effect on X-linked gene expression, because weak dosage

DC proteins achieve diverse chromosome-wide functions through participation in distinct condensin complexes

DC proteins function not only in a condensin complex specialized for dosage compensation (condensin IDC) but also in two other biochemically distinct condensin complexes in C. elegans (condensin I and condensin II) to carry out independent roles in chromosome segregation and meiotic crossover regulation (Figure 3) [10•, 12, 48••, 49]. Condensin I differs from condensin IDC by only one subunit: SMC-4 from condensin II replaces the SMC protein DPY-27 from condensin IDC [10•, 48••]. Condensin I

Conclusions

Fundamental principles have emerged regarding the X-chromosome-specific targeting and loading of a condensin-like DCC to reduce gene expression from both X chromosomes of C. elegans hermaphrodites. Two distinct mechanisms govern DCC binding: sequence-dependent recruitment to autonomous binding sites that confer X-chromosome specificity (rex) and nonautonomous, sequence-independent binding to sites (dox) correlated with high levels of gene expression. The dosage compensation process is

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

BJM thanks T Cline and the Meyer lab for numerous discussions and J Gunther for figure design. This work was supported by NIH grant GM30702. BJM is an investigator of the Howard Hughes Medical Institute.

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