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Non-coding enhancer RNA as a cell/tissue specific therapeutic target

Ty Dale Troutman

Appointment Period: 2015-2016, Grant Year: [29]

troutman

Specific alteration of cancer-cell transcriptional programs could potentially transform patient outcomes by mitigating debilitating therapy-associated morbidity associated with off-target effects. Transcriptional program diversification of various cells and tissues is regulated by employment of cell/tissue specific enhancers. Active enhancers can be defined by transcription of enhancer-associated RNA (eRNA), a noncoding RNA species. The levels of eRNA can be suppressed by treatment of cells with eRNA specific antisense oligonucleotides (ASOs) or bromodomain (BRD) inhibitors, such as JQ1, which function in part by suppressing assembly of transcriptional machinery at the enhancer. BRDs are readers of N-acetyl lysine marks, and represent a family of conserved protein-interaction modules. In vitro, suppression of eRNA levels revealed a causal link between eRNA transcription and nearby gene transcription. Since discrete cell/tissue types employ specific enhancers, they also have specific eRNAs, strongly suggesting that eRNAs are cell-type specific and druggable. Importantly, ASO technology is successfully used clinically to reversibly alter gene expression by targeting gene-coding regions, and several anti- cancer drugs using oligonucleotide technology are in various stages of clinical trials. Further, three BRD inhibitors (TEN-010, GSK525762, and CPI-0610) are in active clinical trials for use as anti-cancer therapeutics. Together, this suggests a potential therapeutic role for eRNA suppression in cancer.

My research encompasses two parallel approaches. First, I will target cell-specific eRNAs as an approach to reversibly alter mRNA expression in a cell-specific manner. This will be accomplished by developing eRNA atlases from purified primary murine liver cell populations (hepatocytes, sinusoidal endothelial cells and Kupffer cells), cell populations previously shown to be ASO-targetable. We will use the eRNA atlases to design specific eRNA targeting ASOs (collaboration with Isis Pharmaceuticals). These ASOs will then be tested in vitro and in vivo for their ability to suppress the targeted eRNA and neighboring gene expression in a cell type specific manner. As a second independent approach, I will follow up studies in our laboratory indicating that BRD inhibitors suppress transcription from a subset of signal-dependent enhancers. Understanding the basis for enhancer specificity will be of general interest and may provide insights for advancing the use of small molecules for enhancer therapy. The results of these efforts will enable a secondary phase of studies testing the therapeutic efficacy ASO targeting or BRD inhibition for modulating the outcomes of cancer models.

PUBLICATIONS (resulting from this training) 

Trainee recently appointed to grant: publications are still in progress.