Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape

Unrestrained receptor tyrosine kinase (RTK) signaling and epigenetic deregulation are root causes of tumorigenesis. We establish linkage between these processes by demonstrating that aberrant RTK signaling unleashed by oncogenic HRasG12V or loss of negative feedback through Sprouty gene deletion remodels histone modifications associated with active typical and super-enhancers. However, although both lesions disrupt the Ras-Erk axis, the expression programs, enhancer signatures, and transcription factor networks modulated upon HRasG12V transformation or Sprouty deletion are largely distinct. Oncogenic HRasG12V elevates histone 3 lysine 27 acetylation (H3K27ac) levels at enhancers near the transcription factor Gata4 and the kinase Prkcb, as well as their expression levels. We show that Gata4 is necessary for the aberrant gene expression and H3K27ac marking at enhancers, and Prkcb is required for the oncogenic effects of HRasG12V-driven cells. Taken together, our findings demonstrate that dynamic reprogramming of the cellular enhancer landscape is a major effect of oncogenic RTK signaling. [Display omitted] •Unrestrained Ras-Erk signaling deregulates histone marking at active enhancers•Sprouty loss and oncogenic HRasG12V alter distinct enhancers and target genes•Gata4 is necessary for HRasG12V-driven enhancer marking and target gene expression•Prkcb and BET bromodomains are necessary for the oncogenic effects of HRasG12V Aberrant receptor tyrosine kinase signaling mediated by oncogenic Ras or loss of Sprouty promotes tumorigenesis. Nabet et al. find that unrestrained receptor tyrosine signaling driven by these lesions alters distinct super-enhancers, transcription factors, and target genes. Gata4 and Prkcb are identified as mediators of the oncogenic program upon Ras transformation.