Two Classes of Dosage Compensation Complex Binding Elements along Caenorhabditis elegans X Chromosomes

Abstract

Dosage compensation equalizes X-linked gene products between the sexes. In Caenorhabditis elegans, the dosage compensation complex (DCC) binds both X chromosomes in XX animals and halves the transcription from each. The DCC is recruited to the X chromosomes by a number of loci, rex sites, and is thought to spread from these sites by an unknown mechanism to cover the rest of the chromosome. Here we describe a novel class of DCC-binding elements that we propose serve as "way stations" for DCC binding and spreading. Both rex sites and way stations comprise strong foci of DCC binding on the native X chromosome. However, rex sites maintain their ability to bind large amounts of DCC even on X duplications detached from the native X, while way stations do not. These results suggest that two distinct classes of DCC-binding elements facilitate recruitment and spreading of the DCC along the X chromosome.In animals with chromosomally determined sex, including mammals, flies, and worms, the process of dosage compensation equalizes transcription of X-linked genes in males (XY or XO) and females (XX), despite their different gene doses (23). Female mammals accomplish this by inactivating most of the genes on one of the two X chromosomes (36), Drosophila males upregulate most genes on the single male X chromosome twofold (26,34), and Caenorhabditis elegans hermaphrodites (XX) halve transcription from each X chromosome (27). Although the details of the dosage compensation mechanisms differ between species, all require chromosome-specific targeting of molecular complexes, and all regulate transcription over large domains. While dosage compensation is one of the best studied models for domain-specific transcriptional regulation, other examples of domain-specific regulation include clusters of imprinted genes (9), coregulation of 20 to 80 gene clusters throughout the human genome (13), coregulation of HOX gene clusters in several organisms (7), and coordinate regulation of the entire fourth chromosome in Drosophila (17, 31). The mechanism by which domain-specific regulatory complexes are recruited to specific regions and function over large distances remains an intriguing question.In C. elegans, the dosage compensation complex (DCC) binds along the entire length of both X chromosomes in XX animals (hermaphrodites) and halves transcription from each (27). The SDC-2, SDC-3, and DPY-30 proteins recruit the condensin-like subcomplex composed of MIX-1, DPY-27, DPY-26, DPY-28, and CAPG-1, as well as the SDC-1 and DPY-21 proteins, to the X chromosome (reviewed in reference 27). The condensin-like subcomplex shares the MIX-1 subunit with the C. elegans mitotic condensin complex, which functions in chromosome condensation and segregation. However, the two complexes have separate functions, and mutations in the gene encoding the DCC-specific subunit dpy-27 do not affect mitosis or meiosis (22,27).Despite the observed DCC binding along the entire length of both hermaphrodite X chromosomes in wild-type animals, some large duplicated X-chromos...

The C. elegans Dosage Compensation Complex Propagates Dynamically and Independently of X Chromosome Sequence

“…Earlier low-resolution studies with X-chromosome DNA attached to an autosome showed that DCC did not spread such that the autosome was engulfed [14, 16, 19, 20]. We investigated different hypotheses for how DCC spreading onto the whole autosome is limited (Figure 5A).…”

“…For example, there is a ChIP-defined DCC focus 173 kb from the end. Regardless, the gradual decline of binding from the fusion site explains the need to have multiple recruitment elements or “way stations” [19] spaced along the X chromosome to maintain the required levels of DCC association with X.…”

Condensins: universal organizers of chromosomes with diverse functions

“…The DCC is composed of a condensin I-like complex (known as condensin I DC ) and another five-subunit complex containing SDC-1, SDC-2, SDC-3, DPY-21, and DPY-30. Experiments combining genome-wide chromatin precipitation assays have revealed that the DCC is enriched at ;1500 sites scattered along the length of the X chromosomes that can be categorized into two different classes: rex (recruiting element on X) sites and dox (dependent on X) sites (McDonel et al 2006;Ercan et al 2007;Blauwkamp and Csankovszki 2009;Jans et al 2009). The rex sites contain a 12-base-pair sequence motif called MEX (motif enriched on X) and are able to recruit the DCC when detached from the X.…”

Caenorhabditis elegans Dosage Compensation Regulates Histone H4 Chromatin State on X Chromosomes

“…The DCC is thought to load across X chromosomes in a two-step manner: binding to a group of high-affinity recruitment sites (rex) and spreading in a transcription-dependent, DNA sequence-independent manner to sites unable to recruit on their own (dox) (15,32). Some rex sites are able to recruit only as extrachromosomal arrays and not as part of a duplication of a small region of X chromosomes (waystations) (5). Condensin I DC is homologous to condensin, the highly conserved mitotic chromosome organization and segregation machinery, suggesting that dosage compensation in the worm is achieved by partial condensation of the X chromosomes.…”