Molecular Genetics of Dosage Compensation in Drosophila

果蝇剂量补偿的分子遗传学

• 批准号: 6401873
• 负责人: Mitzi I Kuroda
• 金额: $ 3.76万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6401873
• 关键词: Drosophilidae; RNA; arthropod genetics; autosome; binding sites; chromatin; chromosome translocation; cooperative study; crosslink; dosage; gene expression; genetic mapping; genetic transcription; genome; immunoprecipitation; intermolecular interaction; molecular genetics; nucleoproteins; sex chromosomes; sex linked trait; subtraction hybridization

DESCRIPTION (provided by applicant) This research will be done primarily in Russia as an extension of NIH grant # R0l GM45744. 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 complex (composed of the MSL proteins, and non-coding roX RNAs). Our focus in this FIRCA proposal, enabled by the cytological expertise of the Zhimulev group, will be to analyze the exquisite X chromosome-specificity of the Drosophila dosage compensation complex. We have recently proposed that in wild type males, the MSL complex forms at approximately 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 remarkable property of spreading in cis will be examined by mapping the sites to which the complex spreads in the endogenous X chromosome, as well as in cases where a transgene carrying a chromatin entry site is inserted ectopically into an autosome. We will also study conditions that affect the ability and site-specificity of MSL spreading, including heat shock, limiting levels of the MSL2 subunit, and the behavior of X:A translocation chromosomes. 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（由申请人提供） 这项研究将主要在俄罗斯进行，作为 NIH 拨款的延伸# R0l GM45744。剂量补偿是两者之间相互作用的一个引人注目的例子 基因特异性调控和染色体结构。这个过程已经进化了 使具有一条 X 染色体的男性中的 X 连锁基因表达相同，并且 女性有两个。在分子水平上检查的物种中，剂量 补偿是由装饰 X 的性别特异性因素介导的 染色体调节染色质结构和基因表达。在果蝇中， 剂量补偿至少部分是通过位点特异性来实现的 组蛋白 H4 乙酰化，由男性特异性、X 特异性复合物调节 （由 MSL 蛋白和非编码 roX RNA 组成）。我们的重点在这方面 FIRCA 提案由 Zimulev 小组的细胞学专业知识支持， 将分析果蝇精致的 X 染色体特异性 剂量补偿复合体。 我们最近提出，在野生型雄性中，MSL 复合体形成于 大约 30 个染色质进入位点，仅沿着 X 分布， 然后被顺式吸引到可能常见的序列或蛋白质上 整个基因组中的活跃基因。这种显着的特性在传播 将通过绘制复合物在体内传播的位点来检查 cis 内源 X 染色体，以及携带 X 染色体的转基因的情况 染色质进入位点异位插入常染色体。我们也会 研究影响 MSL 传播能力和位点特异性的条件， 包括热休克、MSL2 亚基的限制水平以及 X：染色体易位。 在果蝇和人类中，调节分子通常限制在顺式 到 X 染色体，但如果带到常染色体上，则可以在基因上传播 剂量补偿前。剖析这些背后的机制 表观遗传调控过程将提供对许多重要的洞察 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。