MOLECULAR GENETICS OF DOSAGE COMPENSATION IN DROSOPHILA

描述(来自应用程序的逐字)：剂量补偿是一个引人注目的问题 基因特异性调控与染色体相互作用的例子 建筑。这一过程已经进化到使X连锁基因表达 具有一个X染色体的男性和具有两个X染色体的女性的情况相同。在物种上 在分子水平上检查，剂量补偿是由 修饰X染色体以调节染色质的性别特异因素 结构和基因表达。在果蝇中，剂量补偿是实现的， 至少部分地通过位点特异性的组蛋白H4乙酰化，受一种 男性专一性、X专一性蛋白复合体(由MSL蛋白和 可能是非编码的ROX RNA)。我们在下一个授权期的重点将是 了解果蝇剂量的精致X染色体特异性 补偿情结。 我们的实验将测试一种识别X连锁基因的新模型 MSL复合体。我们最近获得的证据表明，在野生型雄性中， MSL复合体在约30个染色质进入位点形成，仅沿 X，然后在顺式中被吸引到可能是常见的序列或蛋白质 激活整个基因组中的基因。这代表着一个重大的变化 长期以来的预期是大多数X连锁基因会有 MSL复合体识别的X特异的增强子样靶序列 互换。我们的模型提出了与哺乳动物剂量的有趣的相似之处 补偿。在苍蝇和人类中，调节分子通常是 仅限于X染色体的顺式染色体，但如果携带到常染色体上，就可以传播 在基因上从来没有剂量补偿过。剖析潜在的机制 这些表观遗传调控过程将提供对许多重要的 生物学问题，包括人类的正常和疾病状态。一流的 多线染色体的空间分辨率，一个确定的起始点 蛋白质和RNA扩散中突变体的可用性 组件使MSL成为确定如何更改的理想模型系统 染色质结构影响复杂生物体的基因表达。

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.