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 HRas(G12V) 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(G12V) transformation or Sprouty deletion are largely distinct. Oncogenic HRas(G12V) 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(G12V)-driven cells. Taken together, our findings demonstrate that dynamic reprogramming of the cellular enhancer landscape is a major effect of oncogenic RTK signaling.
Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Driskill Graduate Program in Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Behnam
B
Nabet
Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Pilib
P
Ó Broin
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Jaime M
JM
Reyes
Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Kevin
K
Shieh
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Charles Y
CY
Lin
Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Christine M
CM
Will
Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Relja
R
Popovic
Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Teresa
T
Ezponda
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
James E
JE
Bradner
Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Mathematical Sciences, Yeshiva University, New York, NY 10033, USA.
Aaron A
AA
Golden
Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: j-licht@northwestern.edu.
Jonathan D
JD
Licht
D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D004742:Enhancer Elements, Genetic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D064546:Protein Kinase C beta / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D006657:Histones; D008565:Membrane Proteins; D010750:Phosphoproteins; C425468:Spry1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D064546:Protein Kinase C beta; D048049:Extracellular Signal-Regulated MAP Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)