An X chromosome balancing act

Trio of papers shed light on the molecular mechanisms underpinning dosage compensation of the X chromosome in male fruit flies

By | March 17, 2006

A chromosome-wide analysis of the binding of a multi-protein complex implicated in dosage compensation across the male X chromosome in Drosophila reveals that regulatory chromatin complexes need not be confined to promoter and intergenic regions, according to a trio of papers published this week in Genes & Development. Though the exact binding motifs have not been identified, the resulting map -- the highest resolution of its kind -- may shed light on how other such complexes target and bind their target sequences as well. "The chromosomal wide analysis into binding sites gives insight into how histone-modifying complexes are localized to their site of action," said Barbara Panning of the University of California, San Francisco, who did not participate in the research. These studies "basically provided the starting point to begin to answer this question," Panning noted. "It's an important step. Huge would not be an understatement." Dosage compensation is the molecular response to unequal X chromosome complements in male (XY) and female (XX) metazoans. Mammals offset that inequality by inactivating one of the two female X chromosomes. Drosophila, in contrast, boost gene expression on the male's single X chromosome. During the studies, the researchers mapped the binding of the dosage compensation complex (DCC), also known as the male specific lethal (MSL) complex, across X chromosomes. The DCC comprises five proteins, including the MOF histone acetyltransferase and an RNA helicase, and two non-coding RNAs. Earlier research using immunostaining of polytene chromosomes had shown that MSL factors localize to the male X chromosome in discrete bands. But which genes the complex was binding remained a mystery. Mitzi Kuroda of Harvard Medical School, Peter Becker of the University of Munich, and Asifa Akhtar of EMBL, led teams that used chromatin immunoprecipitation-microarray (so-called ChIP-chip) approaches to map the binding of the DCC across the entire X chromosome in Drosophila cell lines, embryos, and in larvae. The current analyses identify more than 700 genes as DCC targets and map their binding states across Drosophila development with sub-kilobase resolution. The authors observed that DCC binding is enriched in transcriptionally active genes, with a bias toward the 3' end of the coding regions, and appears to persist even as transcription levels fall throughout development. The localization of binding at the 3' end is puzzling and unexpected, said Dirk Schübeler of the Friedrich-Miescher-Institute for Biomedical Research, Basel, who wrote a Perspective article accompanying the three papers. "We always thought that, if you want to change expression from a particular gene you need to act at the promoter to modify the amount of polymerase that's recruited. But how can this complex achieve up-regulation of a gene if it sits at the 3' end?" Peter Becker, professor of molecular biology at the University of Munich and author of one of the three papers, suggested the DCC complex could be acting to enhance transcription elongation. Such a role is possible, Schübeler agreed, but it isn't clear how an improvement in the speed of elongation could uniformly enhance expression across the chromosome, especially as the genes are not all expressed at the same rate. He noted, however, that if the elongating polymerase reinitiates on the same gene, increasing the speed of the polymerase could then lead to an increase in the total level of processed mRNA. The authors also find that not all active genes are bound, and that the same genes remain bound to the complex throughout development, regardless of transcriptional activity. That, said Akhtar, suggests that additional factors could play a role in dosage compensation. In a fourth paper out Friday (March 17) in Molecular Cell, Akhtar and her colleagues demonstrated that components of the MSL complex associate with members of the nuclear pore complex, and that removal of those proteins prevents localization of the MSL to the X chromosome. "The emerging hypothesis is that maybe chromatin organization is somehow important in regulating dosage compensation," she said, adding that MSLs may help modulate the transcriptional activity of the X chromosome with the help of these additional factors. Now the researchers are working to understand how DCC selects its targets, and what it does once it gets there. "There are tantalizing hints that there may be specific sequences involved in two of the papers," said Panning, "but that remains to be tested." Jeffrey M. Perkel Links within this article A.A. Alekseyenko et al., "High resolution ChIP-chip analysis reveals that the Drosophila MSL complex selectively identifies active genes on the male X chromosome," Genes & Development, March 17, 2006. G.D. Gilfillan et al., "Chromosome-wide gene-specific targeting of the Drosophila Dosage Compensation Complex," Genes & Development, March 17, 2006. G. Legube et al., "X chromosome wide profiling of MSL-1 distribution and dosage compensation in Drosophila," Genes & Development, March 17, 2006. M.L. Phillips, "X chromosomes talk by pairing," The Scientist, January 20, 2006. Mitzi Kuroda Peter Becker Asifa Akhtar Dirk Schübeler, "Dosage compensation in high resolution: Global upregulation through local recruitment," Genes & Development, March 17, 2006. S. Mendjan et al., "Nuclear pore components are involved in the transcriptional regulation of dosage compensation in Drosophila," Molecular Cell, March 17, 2006.

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