MOLECULAR GENETICS OF DOSAGE COMPENSATION IN DROSOPHILA

果蝇剂量补偿的分子遗传学

• 批准号: 6636025
• 负责人: Mitzi I Kuroda
• 金额: $ 13.94万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6636025
• 关键词: Drosophilidae; chromatin; developmental genetics; gender difference; gene dosage; gene expression; genetic mapping; genetic regulation; genetic regulatory element; genetic transcription; nucleoproteins; regulatory gene; sex chromosomes; tissue /cell culture

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.

描述（来自应用程序的逐字记录）：剂量补偿是一个惊人的 基因特异性调控和染色体之间相互作用的例子 建筑学。这个过程已经进化到使X连锁基因表达 具有一条 X 染色体的男性和具有两条 X 染色体的女性是等效的。 就物种而言 在分子水平上进行检查，剂量补偿是由 装饰 X 染色体以调节染色质的性别特异性因子 结构和基因表达。 在果蝇中，实现了剂量补偿， 至少部分地，通过位点特异性组蛋白 H4 乙酰化，由 男性特异性、X 特异性蛋白质复合物（由 MSL 蛋白质和 可能是非编码 roX RNA）。 我们在接下来的资助期内的重点将是 了解果蝇剂量的精致 X 染色体特异性 补偿复合体。 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，仅沿着 X，然后被顺式吸引到可能常见的序列或蛋白质上 整个基因组中的活性基因。 这代表着一个重大的变化 长期以来，大多数 X 连锁基因都会具有 X 特异性、增强子样靶序列被 MSL 复合物识别 跨。 我们的模型与哺乳动物剂量提出了有趣的相似之处 赔偿。 在果蝇和人类中，调节分子通常是 限制在 X 染色体顺式，但如果带到常染色体，可以传播 基因上以前从未有过剂量补偿。 剖析背后的机制 这些表观遗传调控过程将提供对许多重要的见解 生物学问题，包括人类的正常状态和疾病状态。 超棒的 多线染色体的空间分辨率，确定的起始位点 传播，以及蛋白质和 RNA 传播中突变体的可用性 组件使 MSL 复合体成为确定如何变化的理想模型系统 染色质结构影响复杂生物体的基因表达。