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赠款＃的扩展 R0L GM45744。剂量补偿是相互作用的一个惊人例子 基因特异性调节和染色体结构。这个过程已经发展 在一个X染色体和 女性有两个。在分子水平检查的物种中，剂量 补偿是由装饰x的性别特异性因素介导的 调节染色质结构和基因表达的染色体。在果蝇中， 至少部分通过特定地点实现剂量补偿 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 FIRCA提案，由Zhimulev Group的细胞学专业知识启用， 将分析果蝇的精美X染色体特异性 剂量补偿复合物。 我们最近提出，在野生型男性中，MSL复合物形成 大约30个染色质进入位点，仅沿x，仅分布 然后将顺式吸引到可能共有的序列或蛋白质中 整个基因组的活性基因。扩散的非凡财产 将通过映射复合物在其中扩散到的地点来检查顺式 内源性X染色体，以及在携带A的转基因的情况下 染色质输入站点异位插入自染色体。我们也会 影响MSL扩散能力和场地特异性的研究条件， 包括热冲击，MSL2亚基的限制水平以及 X：易位染色体。 在苍蝇和人类中，调节分子通常在顺式中受到限制 到X染色体，但如果将常染色体带入常染色体，则可以传播在永远不会 剂量补偿之前。解剖这些机制 表观遗传调节过程将为许多重要 生物学问题，包括人类的正常和疾病状态。精湛的 多丹染色体的空间分辨率，这是一个定义的起始位点 扩散，以及蛋白质和RNA扩散中突变体的可用性 组件使MSL复合物成为确定如何变化的理想模型系统 在染色质结构中会影响复杂生物的基因表达。