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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA151574-04
Application #
8473177
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Mietz, Judy
Project Start
2010-07-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$359,288
Indirect Cost
$170,089
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Athuluri-Divakar, Sai Krishna; Vasquez-Del Carpio, Rodrigo; Dutta, Kaushik et al. (2016) A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling. Cell 165:643-55
Hart, Jonathan R; Roberts, Thomas C; Weinberg, Marc S et al. (2014) MYC regulates the non-coding transcriptome. Oncotarget 5:12543-54
Ackley, Amanda; Lenox, Alexandra; Stapleton, Kenneth et al. (2013) An Algorithm for Generating Small RNAs Capable of Epigenetically Modulating Transcriptional Gene Silencing and Activation in Human Cells. Mol Ther Nucleic Acids 2:e104
Weinberg, Marc S; Morris, Kevin V (2013) Long non-coding RNA targeting and transcriptional de-repression. Nucleic Acid Ther 23:9-14
Johnsson, Per; Ackley, Amanda; Vidarsdottir, Linda et al. (2013) A pseudogene long-noncoding-RNA network regulates PTEN transcription and translation in human cells. Nat Struct Mol Biol 20:440-6
Roberts, Thomas C; Morris, Kevin V (2013) Not so pseudo anymore: pseudogenes as therapeutic targets. Pharmacogenomics 14:2023-34
Vadaie, Nadia; Morris, Kevin V (2013) Long antisense non-coding RNAs and the epigenetic regulation of gene expression. Biomol Concepts 4:411-5
Vogt, Peter K (2012) Retroviral oncogenes: a historical primer. Nat Rev Cancer 12:639-48
Kolesnichenko, Marina; Hong, Lixin; Liao, Rong et al. (2012) Attenuation of TORC1 signaling delays replicative and oncogenic RAS-induced senescence. Cell Cycle 11:2391-401

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