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

Behnam Nabet, Pilib Ó Broin, Jaime M. Reyes, Kevin Shieh, Charles Y. Lin, Christine M. Will, Relja Popovic, Teresa Ezponda, James E. Bradner, Aaron A. Golden, Jonathan D. Licht

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number1940
Pages (from-to)1300-1313
Number of pages14
JournalCell Reports
Volume12
Issue number8
DOIs
StatePublished - Aug 25 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape'. Together they form a unique fingerprint.

  • Cite this

    Nabet, B., Ó Broin, P., Reyes, J. M., Shieh, K., Lin, C. Y., Will, C. M., Popovic, R., Ezponda, T., Bradner, J. E., Golden, A. A., & Licht, J. D. (2015). Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape. Cell Reports, 12(8), 1300-1313. [1940]. https://doi.org/10.1016/j.celrep.2015.06.078