PT  - JOURNAL ARTICLE
AU  - Kyle T. Siebenthall
AU  - Chris P. Miller
AU  - Jeff D. Vierstra
AU  - Julie Mathieu
AU  - Maria Tretiakova
AU  - Alex Reynolds
AU  - Richard Sandstrom
AU  - Eric Rynes
AU  - Shane J. Neph
AU  - Eric Haugen
AU  - Audra Johnson
AU  - Jemma Nelson
AU  - Daniel Bates
AU  - Morgan Diegel
AU  - Douglass Dunn
AU  - Mark Frerker
AU  - Michael Buckley
AU  - Rajinder Kaul
AU  - Ying Zheng
AU  - Jonathan Himmelfarb
AU  - Hannele Ruohola-Baker
AU  - Shreeram Akilesh
TI  - Cryptic Promoter Activation Drives <em>POU5F1</em> (<em>OCT4</em>) Expression in Renal Cell Carcinoma
AID  - 10.1101/379198
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 379198
4099  - http://biorxiv.org/content/early/2018/07/27/379198.short
4100  - http://biorxiv.org/content/early/2018/07/27/379198.full
AB  - 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.