Abstract
Tumor-initiating stem cells (SCs) exhibit distinct patterns of transcription factors and gene expression compared to healthy counterparts. Here, we show that dramatic shifts in large open-chromatin domain (super-enhancer) landscapes underlie these differences and reflect tumor microenvironment. By in vivo super-enhancer and transcriptional profiling, we uncover a dynamic cancer-specific epigenetic network selectively enriched for binding motifs of a transcription factor cohort expressed in squamous cell carcinoma SCs (SCC-SCs). Many of their genes, including Ets2 and Elk3, are themselves regulated by SCC-SC super-enhancers suggesting a cooperative feed-forward loop. Malignant progression requires these genes, whose knockdown severely impairs tumor growth and prohibits progression from benign papillomas to SCCs. ETS2-deficiency disrupts the SCC-SC super-enhancer landscape and downstream cancer genes while ETS2-overactivation in epidermal-SCs induces hyperproliferation and SCC super-enhancer-associated genes Fos, Junb and Klf5. Together, our findings unearth an essential regulatory network required for the SCC-SC chromatin landscape and unveil its importance in malignant progression.
Highlights
Stem cells (SCs) have the capacity to self-renew and to generate and repair tissues
We show by gain and loss of function and by associated chromatin landscaping, that these factors are essential for driving the chromatin dynamics that define the malignant state and govern tumor maintenance and survival
After fluorescence-activated cell sorting (FACS), purified cells were stably transduced with an integrating retrovirus expressing HRasG12V
Summary
Stem cells (SCs) have the capacity to self-renew and to generate and repair tissues. Advances in genome technologies provide the means to comprehensively analyze transcriptional profiles of SCs and map their epigenetic landscape on a global level. Studies on cultured embryonic stem cells (ESCs) have shown that a special set of large open-chromatin domains, so-called superenhancers (SEs), control expression of genes important to ESC behavior (Whyte et al, 2013; Parker et al, 2013). Studies on a variety of tissue cell lines have shown that another key feature of SEs is a high density of sequence motifs for cell stage-specific transcription factors (TFs). This allows for their cooperative binding, thereby rendering SE-regulated genes sensitive to the key TF cohort. The genes encoding lineage-specific TFs often themselves harbor SEs resulting in a stable feed-forward loop to fuel and maintain the lineage (Whyte et al, 2013; Hnisz et al, 2013; Loven et al, 2013; Chapuy et al, 2013)
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