Small RNA and whole chromosome recognition

小RNA和全染色体识别

• 批准号: 9353839
• 负责人: VICTORIA H MELLER
• 金额: $ 31.71万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9353839
• 关键词: Address; Animals; Architecture; Caenorhabditis elegans; Characteristics; Chromatin; Chromatin Loop; Chromosomal Instability; Chromosomes; Complex; Congenital Abnormality; Control Groups; Dependence; Development; Distant; Dosage Compensation (Genetics); Drosophila genus; Elements; Employee Strikes; Epigenetic Process; Eukaryota; Family; Female; Financial compensation; Funding; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genome; Genome Stability; Goals; Growth and Development function; Histones; Human; Link; Location; Malignant Neoplasms; Mammals; Matrix Attachment Regions; Modeling; Modification; Molecular Conformation; Mus; Nuclear Matrix; Organism; Outcome; Pathology; Pathway interactions; Preparation; Process; Production; Recruitment Activity; Regulation; Repetitive Sequence; Role; Site; Small Interfering RNA; Small RNA; Source; Specific qualifier value; System; Testing; Untranslated RNA; Work; X Chromosome; autosome; chromatin modification; epigenetic regulation; experimental study; fly; genetic linkage; imprint; male; member; novel; scaffold; sex

Abstract Eukaryotic organisms employ epigenetic regulatory systems that are essential for genome stability and gene expression. Disruptions in these systems are associated with a wide range of pathologies, including chromosome instability, birth defects, cancer and developmental abnormalities. An intriguing type of epigenetic regulation, X chromosome dosage compensation, adjusts the expression of X-linked genes in one sex to accommodate the different numbers of X chromosomes in males and females. Dosage compensation has been intensively studied in mice, C. elegans and Drosophila. The striking differences in the compensation strategies of these organisms are usually emphasized. However, all three systems rely on regulatory complexes that are selectively recruited to X chromatin to modulate expression. These complexes, and their actions on chromatin, have been studied in detail. But in no case do we understand how X chromatin is identified with the requisite selectivity. Our long-term goal is to understand how an entire chromosome is identified and regulated. We have found that the siRNA pathway, and siRNAs from a repetitive element that is near-exclusive to the X, promote recognition of X chromatin. Strikingly, one of these elements, when placed on an autosome, recruits compensation to flanking autosomal genes. These elements are candidate matrix attachment regions and participate in long range interactions. The specific hypothesis we will test is that X chromosome recognition in Drosophila is guided by a chromosome-specific architecture, determined by repetitive elements and modulated by the siRNA pathway. This arrangement facilitates spreading of compensation along the chromosome. We propose that this acts cooperatively with well-studied sites that recruit the dosage compensation complex directly. The proposed experiments will 1) establish the role of the siRNA in modification of chromatin at the X-linked repeats, 2) determine the dependence of matrix attachment and long range interactions on these modifications and 3) test the idea that an X-linked locus containing a key member of the dosage compensation complex, as well as X-specific repeats, acts to coordinate epigenetic modification during compensation.

摘要 真核生物采用表观遗传调控系统， 稳定性和基因表达。这些系统中的中断与广泛的 病理学，包括染色体不稳定性、出生缺陷、癌症和发育 异常一种有趣的表观遗传调节，X染色体剂量补偿， 调节一种性别中X连锁基因的表达，以适应不同数量的X染色体。 男性和女性的染色体。剂量补偿已在美国进行了深入研究， mice、C.线虫和果蝇。薪酬策略的显著差异 这些生物通常被强调。然而，这三个系统都依赖于监管 选择性地募集到X染色质以调节表达的复合物。这些 复合物及其对染色质的作用已被详细研究。但我们绝不会 了解X染色质是如何以必要的选择性识别的。我们的长期目标是 了解整个染色体是如何被识别和调控的。我们发现 siRNA途径，以及来自一个重复元件的siRNA，该重复元件对X几乎是排他性的， 识别X染色质。引人注目的是，其中一个元素，当被放置在常染色体上时， 招募补偿侧翼常染色体基因。这些元素是候选矩阵 连接区域并参与远程相互作用。具体的假设，我们将 果蝇的X染色体识别是由染色体特异性的 结构，由重复元件决定并由siRNA途径调节。这 这种排列便于补偿沿着染色体扩散。我们建议 这与充分研究的募集剂量补偿复合物的位点协同作用 直接.所提出的实验将1）确定siRNA在修饰 在X-连锁重复的染色质，2）决定依赖的基质附着和长 范围内的相互作用对这些修改和3）测试的想法，X连锁基因座含有 剂量补偿复合物的一个关键成员，以及X特异性重复序列， 在补偿期间协调表观遗传修饰。