Endogenous Circular RNAs and the Control of Expression of Aging-related Genes

内源性环状RNA与衰老相关基因表达的控制

• 批准号: 8447297
• 负责人: William R Jeck
• 金额: $ 3.3万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-16 至 2015-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8447297
• 关键词: 9p21; Age; Aging; Atherosclerosis; Base Sequence; Binding; Biochemical; Biological Process; CDKN2A gene; Caucasians; Caucasoid Race; Cell Aging; Cell Cycle Regulation; Cell Line; Cerebrovascular Disorders; Chromatin; Chromosomes; Chromosomes, Human, Pair 9; Code; Complex; Coronary Arteriosclerosis; Data Set; Detection; Diabetes Mellitus; Digestion; Disease; Epigenetic Process; Exonuclease; Functional RNA; Gene Expression Profile; Genes; Genetic; Genetic Polymorphism; Genome; Genomics; Haplotypes; Heart Diseases; Hepatitis; Human Genome; Individual; Ischemic Stroke; Lead; Malignant Neoplasms; Messenger RNA; Methods; Modeling; Mus; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Organ; PRC1 Protein; Peripheral Blood Lymphocyte; Play; Polycomb; Population; Production; Proteins; Publishing; RNA; RNA Binding; RNA Helicase; RNA Sequences; RNA Splicing; Repression; Research; Reverse Transcription; Ribosomal RNA; Risk; Role; Single Nucleotide Polymorphism; Testing; Transcript; Tumor Suppressor Proteins; Variant; Virus; Work; age related; base; cDNA Library; cell type; chromatin immunoprecipitation; circular RNA; disorder risk; endometriosis; frailty; genome wide association study; genome-wide; histone modification; interest; member; mortality; next generation; novel; programs; regenerative

DESCRIPTION (provided by applicant): Extensive work has established that the beneficial, anti-cancer function of the p16INK4a tumor suppressor mechanism makes counteracting negative contributions to mammalian aging. Age associated increases of p16INK4a in this model repress the proliferative and regenerative potential of some organ compartments. Though many of the findings demonstrating this counterbalancing effect of p16INK4a were observed in murine models, recent genome wide association studies (GWAS) have independently and repeatedly found associations with single nucleotide polymorphisms (SNPs) proximal to p16INK4a and numerous age-associated conditions, such as frailty, type 2 diabetes, atherosclerotic disease (including myocardial infarction, ischemic stroke, intracranial aneurism and aortic aneurism), and endometriosis. These variants are in strong linkage with haplotypes that overlap ANRIL, a long non-coding RNA of unknown biological function. We have previously demonstrated that ANRIL produces alternatively spliced mRNA and, unexpectedly, circular RNA species, and moreover that expression of some of these species correlate to GWAS identified SNPs. In this work we intend to investigate these species using genome wide and focused approaches. In aim 1 we will assess the association between previously identified polycomb group repressor complex members (SUZ12, CBX7 and MOV10) and circular ANRIL. In aim 2 we will develop and apply a method for genome wide identification of endogenous circular RNA transcripts. Together these will elucidate the role of the little studied circular RNA constituent f the mammalian transcriptome and develop our understanding of the role of important non-coding RNAs relevant to numerous diseases of aging.

描述（由申请人提供）：大量工作已经证实，p16INK4a 肿瘤抑制机制的有益抗癌功能可以抵消对哺乳动物衰老的负面影响。该模型中 p16INK4a 与年龄相关的增加抑制了某些器官区室的增殖和再生潜力。尽管许多研究结果表明 p16INK4a 的这种平衡作用是在小鼠模型中观察到的，但最近的全基因组关联研究 (GWAS) 独立且反复地发现了与 p16INK4a 附近的单核苷酸多态性 (SNP) 和许多与年龄相关的病症的关联，例如虚弱、2型糖尿病、动脉粥样硬化性疾病（包括心肌梗塞、缺血性中风、颅内动脉瘤和主动脉瘤）、和子宫内膜异位症。这些变异与与 ANRIL（一种生物功能未知的长非编码 RNA）重叠的单倍型密切相关。我们之前已经证明，ANRIL 产生选择性剪接的 mRNA，并且出乎意料地产生环状 RNA 种类，而且其中一些种类的表达与 GWAS 识别的 SNP 相关。在这项工作中，我们打算使用全基因组和集中的方法来研究这些物种。在目标 1 中，我们将评估先前确定的多梳组阻遏物复合体成员（SUZ12、CBX7 和 MOV10）与环状 ANRIL 之间的关联。在目标 2 中，我们将开发并应用一种内源环状 RNA 转录本的全基因组鉴定方法。这些将共同阐明哺乳动物转录组中研究较少的环状 RNA 成分的作用，并加深我们对与多种衰老疾病相关的重要非编码 RNA 的作用的理解。