Cryptic Promoter Activation Drives POU5F1 (OCT4) Expression in Renal Cell Carcinoma
| Autor: | Hannele Ruohola-Baker, Shreeram Akilesh, Mark Frerker, Jeff Vierstra, Shane Neph, Jonathan Himmelfarb, Daniel Bates, Richard Sandstrom, Eric Haugen, Chris P. Miller, Julie Mathieu, J. K. Nelson, Maria S. Tretiakova, Morgan Diegel, Yingye Zheng, Audra K. Johnson, Eric Rynes, Kyle Siebenthall, Douglas Dunn, Michael Buckley, Rajinder Kaul, Alex Reynolds |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0303 health sciences
Cancer Biology medicine.disease 3. Good health Chromatin Transcriptome 03 medical and health sciences 0302 clinical medicine Renal cell carcinoma 030220 oncology & carcinogenesis Cancer research medicine Stem cell Gene Transcription factor 030304 developmental biology Epigenomics |
| DOI: | 10.1101/379198 |
| Popis: | Transcriptional dysregulation drives cancer formation but the underlying mechanisms are still poorly understood. As a model system, we used renal cell carcinoma (RCC), the most common malignant kidney tumor which canonically activates the hypoxia-inducible transcription factor (HIF) pathway. We performed genome-wide chromatin accessibility and transcriptome profiling on paired tumor/normal samples and found that numerous transcription factors with a RCC-selective expression pattern also demonstrated evidence of HIF binding in the vicinity of their gene body. Some of these transcription factors influenced the tumor’s regulatory landscape, notably the stem cell transcription factor POU5F1 (OCT4). Unexpectedly, we discovered a HIF-pathway-responsive cryptic promoter embedded within a human-specific retroviral repeat element that drives POU5F1 expression in RCC via a novel transcript. Elevat POU5F1 expression levels were correlated with advanced tumor stage and poorer overall survival in RCC patients. Thus, integrated transcriptomic and epigenomic analysis of even a small number of primary patient samples revealed remarkably convergent shared regulatory landscapes and a novel mechanism for dysregulated expression of POU5F1 in RCC. |
| Databáze: | OpenAIRE |
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