MOLECULAR GENETICS OF DOSAGE COMPENSATION IN DROSOPHILA

对于使用不同染色体（如X和Y）的物种， 决定性别的是性染色体基因表达的均衡化， 最直接和最重要的方面的性别分化。这是 这被称为剂量补偿，在果蝇中，它是通过两个- 男性X染色体连锁基因的折叠调节。 大型非编码 roX 1和roX 2 RNA（X上的RNA）具有共同的特征，表明在 这一过程，其中最引人注目的是，两个转录本结合 沿着男性X染色体的长度。 本项目的长期目标是了解 通过其染色体被选择性地补偿。拟议实验 关注roX RNA的作用。 最初，遗传相互作用 roX 1和roX 2之间，以及这些基因和男性特异性 将确定补偿所需的致死量（MSLS）， （具体目标一）。 roX基因受到msls的正调控，揭示了一种新的基因表达模式。 MSLS功能的以前未知的方面。 roX的规则 基因将在具体目标II中进一步探索。 的产品 msl作为核糖核蛋白复合物与男性X染色体结合。 在 特异性目的III：msls复合物的RNA组分，其可 包括已知roX RNA。 具体目标三和 IV开始寻找roX基因家族的新成员。 这 这些信息对于理解这些RNA的功能至关重要。 与果蝇相反，人类的补偿涉及失活 女性的X染色体 然而，这两种生物似乎 使用类似的机制，如组蛋白乙酰化， 转录。 另外，两种物质选择性地涂覆改性的聚乙烯。 染色体与RNA 大的Xist转录本与的长度绑定 哺乳动物雌性体内失活的X染色体， 失活。 这些相似之处表明， 果蝇的剂量补偿机制与其他 全球转录调控系统。

For species which use divergent chromosomes (such as X and Y) to determine sex, equalization of sex chromosome gene expression is the most immediate and vital aspect of sexual differentiation. This is termed dosage compensation, and in Drosophila it is achieved by a two- fold up regulation of X-linked genes in the male. The large, non-coding roX1 and roX2 RNAs (RNA on the X) share features suggesting a role in this process, the most striking of which is that both transcripts bind along the length of the male X chromosome. The long term objective of this project is to understand the mechanism by which a chromosome is selectively compensated. Proposed experiments focus on the role of roX RNAs. Initially the genetic interactions between roX1 and roX2, and between these genes and the male-specific lethals (msls), which are required for compensation, will be determined (Specific Aim I). The roX genes are positively regulated by the msls, revealing a previously unknown aspect of the msls function. Regulation of the roX genes will be further explored in Specific Aim II. The products of the msls bind to the male X chromosome as a ribonucleoprotein complex. In Specific Aim III the RNA component of the msls complex, which may include known roX RNAs, will be characterized. Specific Aims III and IV initiate a search for new members of the roX gene family. This information is vital to understanding the function of these RNAs. In contrast to Drosophila, compensation in humans involves inactivation of one of the female X chromosomes. However, both organisms appear to use similar mechanisms, such as histone acetylation, to modify transcription. Additionally, both species selectively coat the modified chromosome with RNA. The large Xist transcript binds to the length of the inactivated X in mammalian females, and is essential for the process of inactivation. These similarities suggest that understanding the mechanism of dosage compensation in Drosophila has relevance to other systems of global transcriptional regulation.