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

20 Citations (Scopus)

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 HRas<sup>G12V</sup> 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 HRas<sup>G12V</sup> transformation or Sprouty deletion are largely distinct. Oncogenic HRas<sup>G12V</sup> 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 HRas<sup>G12V</sup>-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

Fingerprint

Deregulation
Receptor Protein-Tyrosine Kinases
Histones
Transcription Factors
Histone Code
Acetylation
Gene Deletion
Epigenomics
Gene expression
Lysine
Carcinogenesis
Phosphotransferases
Genes
Feedback
Gene Expression

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Nabet, B., Ó Broin, P., Reyes, J. M., Shieh, K., Lin, C. Y., Will, C. M., ... 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

Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape. / Nabet, Behnam; Ó Broin, Pilib; Reyes, Jaime M.; Shieh, Kevin; Lin, Charles Y.; Will, Christine M.; Popovic, Relja; Ezponda, Teresa; Bradner, James E.; Golden, Aaron A.; Licht, Jonathan D.

In: Cell Reports, Vol. 12, No. 8, 1940, 25.08.2015, p. 1300-1313.

Research output: Contribution to journalArticle

Nabet, B, Ó Broin, P, Reyes, JM, Shieh, K, Lin, CY, Will, CM, Popovic, R, Ezponda, T, Bradner, JE, Golden, AA & Licht, JD 2015, 'Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape', Cell Reports, vol. 12, no. 8, 1940, pp. 1300-1313. https://doi.org/10.1016/j.celrep.2015.06.078
Nabet B, Ó Broin P, Reyes JM, Shieh K, Lin CY, Will CM et al. Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape. Cell Reports. 2015 Aug 25;12(8):1300-1313. 1940. https://doi.org/10.1016/j.celrep.2015.06.078
Nabet, Behnam ; Ó Broin, Pilib ; Reyes, Jaime M. ; Shieh, Kevin ; Lin, Charles Y. ; Will, Christine M. ; Popovic, Relja ; Ezponda, Teresa ; Bradner, James E. ; Golden, Aaron A. ; Licht, Jonathan D. / Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape. In: Cell Reports. 2015 ; Vol. 12, No. 8. pp. 1300-1313.
@article{7d3302b1482842f3a5c7235230323d16,
title = "Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape",
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.",
author = "Behnam Nabet and {{\'O} Broin}, Pilib and Reyes, {Jaime M.} and Kevin Shieh and Lin, {Charles Y.} and Will, {Christine M.} and Relja Popovic and Teresa Ezponda and Bradner, {James E.} and Golden, {Aaron A.} and Licht, {Jonathan D.}",
year = "2015",
month = "8",
day = "25",
doi = "10.1016/j.celrep.2015.06.078",
language = "English (US)",
volume = "12",
pages = "1300--1313",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "8",

}

TY - JOUR

T1 - Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape

AU - Nabet, Behnam

AU - Ó Broin, Pilib

AU - Reyes, Jaime M.

AU - Shieh, Kevin

AU - Lin, Charles Y.

AU - Will, Christine M.

AU - Popovic, Relja

AU - Ezponda, Teresa

AU - Bradner, James E.

AU - Golden, Aaron A.

AU - Licht, Jonathan D.

PY - 2015/8/25

Y1 - 2015/8/25

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84939780724&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84939780724&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2015.06.078

DO - 10.1016/j.celrep.2015.06.078

M3 - Article

AN - SCOPUS:84939780724

VL - 12

SP - 1300

EP - 1313

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 8

M1 - 1940

ER -