Activation of silenced tumor suppressor genes by non-coding RNA

项目摘要 在过去的几年里，很明显，相当大比例的人类基因与 它们各自的天然反义转录本，与转录的蛋白质编码RNA重叠 方向。大量证据表明，这些长长的反义非编码转录本 积极参与蛋白质编码的正义RNA转录和RNA加工的调节 级别。反义转录的广泛出现证明了基因调控的普遍存在 天然反义转录本。反义非编码RNA与肿瘤沉默有关 抑制基因。我们小组(2)以及其他小组(3)最近的研究表明，表观遗传学 肿瘤抑制基因的沉默是双向，即正义水平不平衡的结果 和反义转录。在这里，我们建议研究长的非编码反义RNA在基因中的作用 沉默和基因激活。我们将识别和表征具有代表性的长非编码成绩单 沉默的肿瘤抑制基因。然后我们将通过以下方式重新激活沉默的肿瘤抑制基因的转录 干扰反义转录本的活性并确定其分子机制。 激活。我们还将确定肿瘤抑制基因重新激活对细胞表型的影响。这 这项工作将增加我们对肿瘤抑制因子沉默的理解，通过恢复沉默状态将 提供新的治疗和诊断方法。

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.