Noncoding RNAs and Chromatin Structure

非编码 RNA 和染色质结构

• 批准号: 6808753
• 负责人: RICHARD L KELLEY
• 金额: $ 28.97万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6808753
• 关键词: Drosophilidae; RNA; cell biology; chromatin; cytology; gene dosage; gene expression; genetic regulation; lethal genes; nucleic acid sequence; polymerase chain reaction; sex chromosomes

DESCRIPTION (provided by applicant): Much of a cell's DNA is transcriptionally silent because it is packaged in an inaccessible chromatin architecture. Chromatin remodeling enzymes play critical roles in preparing appropriate genes for transcription in the correct cell type by covalently modifying the flexible tails of histones that stick out of the nucleosomes and contact DNA. Altering chromatin architecture has major medical implications. Some cancers are at least in part due to epigenetic silencing of a tumor suppressor gene whose DNA sequence remains wild type. Likewise, several debilitating inherited diseases are caused by problems in imprinted genes where a wild type allele is present but silent. Finally, a major obstacle to successful gene therapy is the fact the even if exogenous DNA enters a cell, it often has no therapeutic effect because the gene is packaged in silent chromatin. The Drosophila MSL (male-specific lethal) dosage compensation complex provides an outstanding model system to study chromatin modifications because, 1) it acts on more than a thousand unrelated genes on the X chromosome, but not the autosomes, 2) its major MSL protein and roX RNA components have been identified, 3) the change in gene expression is very subtle, only two-fold, 4) the MSL complex is only required in males, allowing in vivo analysis of inactive partial/mutant complexes in females, and 5) the superb cytology of polytene chromosomes provides unequaled material to study target recognition in vivo. The MSL proteins and roX RNAs will be functionally dissected by characterizing mutants in vivo. The MSL complex is held as a model of epigenetic regulation because of its spectacular spreading behavior that can be directly visualized on polytene chromosomes. A new model to explain how cis spreading operates will be tested. New search methods will be developed to identify currently unknown noncoding RNAs.

描述（由申请人提供）：细胞的大部分DNA在转录上保持沉默，因为它包装在无法接近的染色质体系结构中。染色质重塑酶通过共价修饰组蛋白的柔性尾巴和接触DNA的柔性尾巴，从而在正确的细胞类型中制备适当的基因进行转录中起关键作用。改变染色质体系结构具有主要的医学意义。一些癌症至少部分是由于肿瘤抑制基因的表观遗传沉默，其DNA序列仍然是野生型。同样，几种使人衰弱的遗传疾病是由存在野生型等位基因但保持沉默的烙印基因的问题引起的。最后，成功基因疗法的主要障碍是，即使外源性DNA进入细胞，它通常也没有治疗作用，因为该基因已包装在静音染色质中。果蝇MSL（男性特异性致死）剂量补偿复合物为研究染色质修饰提供了出色的模型系统，因为，1）它在X染色体上作用于X染色体上的一千多个无关的基因，但不是常染色体，2）它的主要MSL蛋白和ROX RNA成分仅在基因中，3）仅在基因上进行了次数，3）仅在4）中被识别出4）。雄性，可以在女性中对不活跃的部分/突变体复合物进行体内分析，以及5）多丹染色体的精美细胞学提供了无与伦比的材料，可以在体内研究目标识别。 MSL蛋白和ROX RNA将通过表征体内突变体来剖析功能。 MSL复合物被视为表观遗传调节的模型，因为它具有壮观的扩散行为，可以直接在多丁烯染色体上观察到。将如何测试一个新模型来解释CIS扩散的运作方式。将开发新的搜索方法来识别当前未知的非编码RNA。