Small RNA and whole chromosome recognition in Drosophila melanogaster.

描述（由申请人提供）：真核生物采用一套表观遗传调控系统，这些系统对基因组稳定性和正常基因表达至关重要。表观遗传系统的破坏与广泛的病理学有关，包括染色体不稳定性、出生缺陷、癌症和发育异常。一种有趣的表观遗传调节类型，X染色体剂量补偿，调节一种性别中X连锁基因的表达，以适应男性和女性中不同数量的X染色体。剂量补偿已经在小鼠中进行了深入的研究，C。线虫和果蝇。这些生物体的剂量补偿策略的显着差异通常被强调。然而，这三种系统都依赖于染色质调节复合物，这些复合物选择性地募集到X染色体上以调节表达。这些复合物及其对染色质的作用已被详细研究。但是，在任何情况下，我们都不知道X染色质是如何以必要的选择性被识别的。我们的长期目标是了解整个染色体是如何识别和调节的。我们将检验的具体假设是，果蝇的X染色体识别涉及小RNA。我们的研究表明，双向转录的卫星序列，是接近排他性的X染色体响应一个强大的遗传修饰剂的补偿。我们假设遗传修饰剂通过siRNA发挥其作用。拟议的实验将确定小RNA途径和X连锁卫星在剂量补偿中的作用。将追求三个具体目标以确定1）RNAi是否通常影响X染色质和剂量补偿，2）X连锁卫星是否是RNAi的来源和/或靶，以及3）X连锁卫星是否有助于位于附近的基因的剂量补偿。我们建议RNAi作用于先前鉴定的元件之前或与先前鉴定的元件平行，这些元件在X染色体上适度富集，以确保X染色质的排他性识别。 公共卫生相关性：基因组的适当调控需要协调控制与整个染色体一样大的基因组。这项提案将调查的想法，小的非编码RNA（RNAi），作用于重复序列，是有限的特定染色体，是一个内在的功能，这一过程在苍蝇。果蝇和哺乳动物中类似过程的相似性表明，这种机制也可能有助于人类正常的基因组调控。

DESCRIPTION (provided by applicant): Eukaryotic organisms employ a suite of epigenetic regulatory systems that are essential for genome stability and normal gene expression. Disruptions in epigenetic 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 dosage compensation strategies of these organisms are usually emphasized. However, all three systems rely on chromatin regulatory complexes that are selectively recruited to the X chromosome to modulate expression. These complexes, and their actions on chromatin, have been studied in great 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. The specific hypothesis we will test is that X chromosome recognition in Drosophila involves small RNAs. Our studies reveal that bi-directionally transcribed satellite sequences that are near-exclusive to the X chromosome respond to a potent genetic modifier of compensation. We postulate that the genetic modifier exerts its effect through siRNA. The proposed experiments will determine the role of small RNA pathways and X-linked satellites in dosage compensation. Three specific aims will be pursued to determine if 1) RNAi normally influences X chromatin and dosage compensation, 2) if X-linked satellites are sources and/or targets of RNAi, and 3) if X- linked satellites contribute to the dosage compensation of genes situated nearby. We propose that RNAi acts prior to, or in parallel with previously identified elements, which are modestly enriched on the X chromosome, to ensure exclusive recognition of X chromatin. PUBLIC HEALTH RELEVANCE: 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 non- coding RNA (RNAi), acting on repetitive sequences that are limited to particular chromosomes, is an intrinsic feature this process in flies. The similarities between analogous processes in flies and mammals suggest that this mechanism may also contribute to normal genome regulation in humans.