Activation of silenced tumor suppressor genes by non-coding RNA

非编码RNA激活沉默的肿瘤抑制基因

• 批准号: 8096834
• 负责人: PETER K VOGT
• 金额: $ 38.22万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8096834
• 关键词: Antisense RNA; Biological Markers; Code; Development; Epigenetic Process; Functional RNA; Gene Activation; Gene Expression Regulation; Gene Silencing; Genes; Genetic Transcription; Human; Lead; Malignant Neoplasms; Molecular; Phenotype; Play; Prevalence; Proteins; RNA; RNA Processing; Regulation; Research; Role; Tissue-Specific Gene Expression; Transcript; Transcription Process; Tumor Suppressor Genes; Tumor Suppressor Proteins; Validation; Work; cancer diagnosis; cancer therapy; novel diagnostics; novel strategies; novel therapeutics; public health relevance; tumorigenesis

DESCRIPTION (provided by applicant): Over the last few years, it has become evident that a significant proportion of human genes are associated with their respective natural antisense transcript, which overlaps the protein coding RNA transcribed in the sense direction. A body of evidence has emerged demonstrating that these long antisense non-coding transcripts actively participate in the regulation of protein-coding sense RNA transcription and RNA processing at various levels. The widespread occurrence of antisense transcription documents the prevalence of gene regulation by natural antisense transcripts. Antisense non-coding RNAs have been implicated in the silencing of tumor suppressor genes. The recent studies by our group (2) as well as others (3) suggest that the epigenetic silencing of tumor suppressor genes is the result of an imbalance between the levels of bidirectional, i.e. sense and antisense, transcription. Here, we propose to study the roles of long non-coding antisense RNAs in gene silencing and in gene activation. We will identify and characterize long non-coding transcripts for representative silenced tumor suppressor genes. We will then re-activate the transcription of silenced tumor suppressors by interfering with the activity of antisense transcripts and determine the molecular mechanism of this re- activation. We will also determine the effects of tumor suppressor re-activation on the cellular phenotype. This work will increase our understanding of tumor suppressor silencing and by reverting the silenced state will provide new therapeutic and diagnostic approaches. PUBLIC HEALTH RELEVANCE: We propose to identify and characterize long non-coding RNAs that are associated with silenced tumor suppressor genes in cancer. We hypothesize that these non-coding transcripts play a critical regulatory role in determining differential gene expression in cancer and will validate these regulatory activities of antisense transcripts on representative tumor suppressor genes. The results of this research will contribute to a mechanistic understanding of epigenetic changes in cancer and provide basic information for the development of new approaches to cancer diagnosis and treatment.

描述（由申请人提供）：在过去的几年中，已经很明显人类基因与它们各自的自然反义转录物相关，这与在感觉方向转录的蛋白质编码RNA重叠。已经出现了一大批证据，表明这些长期反义的非编码转录本积极参与蛋白质编码的RNA转录和不同级别的RNA处理的调节。反义转录文件的广泛发生是自然反义转录物调节基因调节的普遍性。反义非编码RNA与肿瘤抑制基因的沉默有关。我们小组（2）以及其他（3）的最新研究表明，肿瘤抑制基因的表观遗传沉默是双向的水平（即感觉和反义，转录）之间不平衡的结果。在这里，我们建议研究长无编码反义RNA在基因沉默和基因激活中的作用。我们将确定并表征代表性沉默的抑制肿瘤基因的长期非编码转录本。然后，我们将通过干扰反义转录物的活性来重新激活沉默的肿瘤抑制器的转录，并确定这种恢复的分子机制。我们还将确定肿瘤抑制剂重新激活对细胞表型的影响。这项工作将增加我们对抑制肿瘤沉默的理解，并通过重新降低沉默的状态将提供新的治疗方法和诊断方法。 公共卫生相关性：我们建议识别和表征与癌症中沉默的肿瘤抑制基因相关的长期非编码RNA。我们假设这些非编码转录本在确定癌症中差异基因表达方面起着关键的调节作用，并将验证反义转录本上对代表性肿瘤抑制基因的调节活性。这项研究的结果将有助于对癌症表观遗传变化的机械理解，并为开发癌症诊断和治疗的新方法提供基本信息。