Eukaryotic organisms employ epigenetic regulatory systems that are essential for genome stability and gene expression. Disruptions in these systems are associated with a wide range of pathologies, including chromosome instability, birth defects, cancer and developmental abnormalities. An intriguing type of epigenetic regulation, X chromosome dosage compensation, adjusts the expression of X-linked genes in one sex to accommodate the different numbers of X chromosomes in males and females. Dosage compensation has been intensively studied in mice, C. elegans and Drosophila. The striking differences in the compensation strategies of these organisms are usually emphasized. However, all three systems rely on regulatory complexes that are selectively recruited to X chromatin to modulate expression. These complexes, and their actions on chromatin, have been studied in detail. But in no case do we understand how X chromatin is identified with the requisite selectivity. Our long-term goal is to understand how an entire chromosome is identified and regulated. We have found that the siRNA pathway, and siRNAs from a repetitive element that is near-exclusive to the X, promote recognition of X chromatin. Strikingly, one of these elements, when placed on an autosome, recruits compensation to flanking autosomal genes. These elements are candidate matrix attachment regions and participate in long range interactions. The specific hypothesis we will test is that X chromosome recognition in Drosophila is guided by a chromosome-specific architecture, determined by repetitive elements and modulated by the siRNA pathway. This arrangement facilitates spreading of compensation along the chromosome. We propose that this acts cooperatively with well-studied sites that recruit the dosage compensation complex directly. The proposed experiments will 1) establish the role of the siRNA in modification of chromatin at the X-linked repeats, 2) determine the dependence of matrix attachment and long range interactions on these modifications and 3) test the idea that an X-linked locus containing a key member of the dosage compensation complex, as well as X-specific repeats, acts to coordinate epigenetic modification during compensation.
Proper regulation of the genome requires coordinated control of groups of genes as large as an entire chromosome. This proposal will investigate the idea that small RNA modulates the architecture of the fly X chromosome to facilitate coordinated regulation of the genes on this chromosome. The similarities between analogous processes in flies and mammals suggest that similar mechanisms contribute to normal genome regulation in humans.
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