Activation of silenced tumor suppressor genes by non-coding RNA

描述（由申请人提供）：在过去的几年里，很明显，很大一部分人类基因与它们各自的天然反义转录物相关，这些转录物与在义方向转录的蛋白质编码RNA重叠。大量证据表明，这些长反义非编码转录物在不同水平上积极参与蛋白质编码意义RNA转录和RNA加工的调控。反义转录的广泛存在证明了自然反义转录物调控基因的普遍存在。反义非编码rna与肿瘤抑制基因的沉默有关。我们小组(2)和其他人(3)最近的研究表明，肿瘤抑制基因的表观遗传沉默是双向（即正义和反义）转录水平失衡的结果。在此，我们拟研究长链非编码反义rna在基因沉默和基因激活中的作用。我们将鉴定和表征具有代表性的沉默肿瘤抑制基因的长非编码转录本。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子的转录，并确定这种重新激活的分子机制。我们还将确定肿瘤抑制因子再激活对细胞表型的影响。这项工作将增加我们对肿瘤抑制基因沉默的理解，通过恢复沉默状态将提供新的治疗和诊断方法。

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.