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

基本信息

批准号：
8676713
负责人：
PETER K VOGT
金额：
$ 37.08万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-12-31
项目状态：
已结题

项目摘要

Project Summary 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.

项目摘要在过去的几年中，很明显人类基因与它们各自的自然反义转录本，这与从某种意义上转录的蛋白质编码RNA重叠方向。出现了大量证据，表明这些长的反义非编码转录本积极参与各种蛋白质编码的RNA转录和RNA处理水平。反义转录文件的广泛发生是基因调节的普遍性自然反义转录本。反义非编码RNA与肿瘤的沉默有关抑制基因。我们小组（2）以及其他研究（3）的最新研究表明表观遗传沉默抑制肿瘤基因是双向水平之间的不平衡的结果，即和反义，转录。在这里，我们建议研究长无编码反义RNA在基因中的作用沉默和基因激活。我们将确定并表征代表性的长期非编码转录本沉默的肿瘤抑制基因。然后，我们将重新激活通过干扰反义转录的活性，并确定该重新的分子机制激活。我们还将确定肿瘤抑制剂重新激活对细胞表型的影响。这工作将增加我们对抑制肿瘤抑制沉默的理解，并通过重现沉默的状态提供新的治疗和诊断方法。