MOLECULAR GENETICS OF DOSAGE COMPENSATION IN DROSOPHILA

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DESCRIPTION (verbatim from the application): Dosage compensation is a striking example of the interplay between gene-specific regulation and chromosomal architecture. This process has evolved to make X-linked gene expression equivalent in males with one X chromosome and females with two. In species examined at the molecular level, dosage compensation is mediated by sex-specific factors that decorate the X chromosomes to regulate chromatin structure and gene expression. In Drosophila, dosage compensation is achieved, at least in part, through site-specific histone H4 acetylation, modulated by a male-specific, X-specific protein complex (composed of the MSL proteins, and possibly non-coding roX RNAs). Our focus in the coming grant period will be to understand the exquisite X chromosome-specificity of the Drosophila dosage compensation complex. Our experiments will test a new model for the recognition of X linked genes by the MSL complex. We recently obtained evidence that in wild type males, the MSL complex forms at ~30 chromatin entry sites, distributed exclusively along the X, and is then attracted in cis to sequences or proteins that may be common to active genes throughout the genome. This represents a significant change from the longstanding expectation that most X-linked genes would have X-specific, enhancer-like target sequences recognized by the MSL complex in trans. Our model raises interesting parallels with mammalian dosage compensation. In both flies and humans, regulatory molecules are normally restricted in cis to the X chromosome, but if brought to autosomes, can spread on genes never before dosage compensated. Dissecting the mechanisms underlying these epigenetic regulatory processes will provide insight into many important biological problems, including normal and disease states in humans. The superb spatial resolution of polytene chromosomes, a defined initiation site for spreading, and the availability of mutants in the protein and RNA spreading components make the MSL complex an ideal model system to determine how changes in chromatin architecture affect gene expression in complex organisms.