Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape [RNA-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE63497 | GEO | 2015/08/22
SECONDARY ACCESSION(S): PRJNA268066
REPOSITORIES: GEO
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Project description: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, while 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. We performed ChIP-seq to assess the global changes in the histone modifications H3K27ac (AC), H3K4me1 (me1), and H3K4me3 (me3) upon loss of feedback regulation through Sprouty (Spry) deletion, and upon unrestrained signaling driven by oncogenic HRasG12V. ChIP-seq was performed in biological duplicate; replicate2 is indicated in the sample name. Spry124fl/fl (VEC) and Spry124-/- (CRE) MEFs were profiled in three conditions: unsynchronized (U), serum starved (S), and serum starved and FGF treated (F). Spry124fl/fl (VEC) MEFs transduced with empty vector (EV) control or HRasG12V (HRas) were profiled in the unsynchronized state.
2015-08-22 | E-GEOD-64190 | biostudies-arrayexpress
Project description: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, while 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.
2015-08-22 | GSE64190 | GEO
Project description: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, while 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. We assessed gene expression changes upon loss of feedback regulation through Sprouty (Spry) deletion, and upon unrestrained signaling driven by mutant oncogenes. RNA-seq was performed in biological triplicate; replicate number is included in the sample name. Spry124fl/fl (VEC) and Spry124-/- (CRE) MEFs were profiled in three conditions: unsynchronized (U), serum starved (S), and serum starved and FGF treated (F). Spry124fl/fl (VEC) MEFs transduced with empty vector (EV) control or the indicated oncogenes (KRasG12V, HRasG12V, and BRafV600E) as well as Spry124-/- (CRE) MEFs transduced with EV control were profiled in the unsynchronized state.
2015-08-22 | E-GEOD-63497 | biostudies-arrayexpress
Project description:Through integration of GATA4 genome-wide occupancy and RNA-seq dataset in embryonic conditional knockout heart, we identified a class of the master cardiac regulator GATA4 bound enhancers. With combinatorial assembly of chromatin signatures, we further refined that a unique type of fetal distal GATA4 enhancers enriched for H3K27ac, H3K4me1, but not for H3K4me3 and RNA polymerase II, are reinstated in adult hypertrophic heart. Study Gata4 and histone modifications in E12.5, Adult, Banding and Sham, and to correlate to gene expression and heart function
2014-08-13 | E-GEOD-52123 | biostudies-arrayexpress
Project description:Oncogenic transformation of individual cell fates by developmental signaling cascades and transcription factors triggers diverse cancer types. Chordoma is a rare, aggressive tumor arising from transformed notochord remnants. Various potentially oncogenic factors have been found deregulated in chordoma and its metastases, yet clear causation remains uncertain. In particular, expression of the notochord-controlling transcription factor Brachyury is hypothesized as key molecular driver in chordoma formation, yet an in vivo model to causally test its oncogenic potential in the notochord is missing. Here, we apply a zebrafish model of chordoma onset to identify the notochord-transforming potential of tumor-implicated candidate genes in vivo. We find that overexpression of human and zebrafish Brachyury, including a version with augmented transcriptional activity, is insufficient to initiate notochord hyperplasia in vivo. In contrast, the repeatedly chordoma-implicated receptor tyrosine kinase (RTK) genes EGFR and KDR/VEGFR2 are sufficient to transform developmental notochord cells, akin to direct activation of Ras. Analysis of transcriptome and sub-cellular organization from transformed notochords suggests that aberrant activation of RTK/Ras signaling attenuates processes required for the differentiation of notochord cells. Taken together, our results provide first in vivo indication for a lack of tumor-initiating potential of Brachyury expression in the notochord, and suggest activated RTK signaling as potent hyperplasia-initiating event in chordoma.
2018-12-01 | E-MTAB-7349 | biostudies-arrayexpress
Project description:Through integration of GATA4 genome-wide occupancy and RNA-seq dataset in embryonic conditional knockout heart, we identified a class of the master cardiac regulator GATA4 bound enhancers. With combinatorial assembly of chromatin signatures, we further refined that a unique type of fetal distal GATA4 enhancers enriched for H3K27ac, H3K4me1, but not for H3K4me3 and RNA polymerase II, are reinstated in adult hypertrophic heart.
2014-08-13 | GSE52123 | GEO
Project description:Background: Signaling by receptor tyrosine kinases (RTK) is frequently dysregulated in gliomas. Inter-individual variability in the causes for dysregulated RTK signaling may have hampered the efficacy of targeted therapies. Using gene expression modules around key regulators in the RAS-RAF-MEK-MAPK cascade and in the phosphatidylinositol 3-kinase-AKT pathways, we developed a âRMPAâ clustering scheme to distinguish gliomas with varying extents of RTK signaling. Results: We identified gene modules consistently co-expressed with NF1 (NF1-M), Sprouty (SPRY-M) and PTEN (PTEN-M) in gliomas. Their signatures enabled robust clustering of adult diffuse gliomas of WHO grades II-IV into RMPAhigh and RMPAlow phenotypes in a morphology-independent manner. In five independent data sets from three continents containing more than 1500 adult diffuse gliomas, RMPAhigh gliomas were associated with poor prognosis while RMPAlow gliomas were not. The RMPAhigh and RMPAlow glioma subtypes showed distinct levels of the activities of RAS-RAF-MEK-MAPK cascade and PI3K-AKT pathway and harbored unique sets of genomic alterations in the RTK signaling-related genes. The RMPAhigh gliomas contained large numbers of immature vessel cells and tumor associated macrophages and both cell types expressed high levels of pro-angiogenic RTKs including MET, VEGFR1, KDR, EPHB4 and NRP1. Conclusion: Inter-glioma variability in RTK signaling activities can be defined using the RMPA clustering scheme. The combined signatures of NF1-M, SPRY-M and PTEN-M reflect RTK signaling activity both in the glioma cells and in the glioma microenvironment. Our data show that RTK signaling in the glioma microenvironment may play a pivotal role in glioma progression. Transcriptome data from 22 fresh gliomas (2 astrocytoma II, 1 oligodendrocytoma II, 7 oligoastrocytoma II, 4 anaplastic oligoastrocytoma III and 8 GBM) were obtained using Affymetrix Human Gene 1.0 ST Array. Unsupervised hierarchical clustering of the expression data for the SPRY-M, NF1-M and PTEN-M was performed on these transcriptome data to identify samples with RMPAhigh or RMPAlow signature.
2015-10-30 | E-GEOD-74462 | biostudies-arrayexpress
Project description:Healthy skin is a tapestry of wild-type and mutant clones. Although injury can cooperate with Ras mutations to promote tumorigenesis, the consequences in genetically mosaic skin are unknown. Here, we show that wild-type cells suppress oncogenic Ras-induced aberrant growth after injury. While HrasG12V/+ and KrasG12D/+ cells outcompete wild-type cells in uninjured, mosaic tissue, their expansion is prevented after injury due to an increase in the fraction of proliferating wild-type cells. Mechanistically, we show that, unlike HrasG12V/+ cells, wild-type cells respond to autocrine and paracrine secretion of EGFR ligands, and this differential activation of the EGFR pathway explains the competitive switch during injury-repair. Inhibition of EGFR by both drug and genetic approaches diminished the proportion of dividing wild-type cells after injury, leading to the expansion of HrasG12V/+ cells. Increased wild-type cell proliferation through a global loss of the cell cycle inhibitor p21 counteracted the expansion of HrasG12V/+ cells even without injury. Thus, injury plays an unanticipated role in switching the competitive balance between oncogenic and wild-type cells in genetically mosaic skin.
2023-03-31 | GSE195892 | GEO
Project description:Super-enhancers and stretch enhancers (SEs) drive expression of genes that play prominent roles in normal and disease cells, but the functional importance of these clustered enhancer elements is poorly understood, so it is not clear why genes key to cell identity have evolved regulation by such elements. Here we show that super-enhancers consist of functional constituent units that concentrate multiple developmental signaling pathways at key pluripotency genes in embryonic stem cells and confer responsiveness to signaling of their associated genes. Cancer cells frequently acquire SEs at genes that promote tumorigenesis, and we show that these genes are especially sensitive to perturbation of oncogenic signaling pathways. Super-enhancers thus provide a platform for signaling pathways to regulate genes that control cell identity during development and tumorigenesis. ChIP-Seq for H3K27ac and RNA Pol II in mouse embryonic stem cells with CRISPR-deleted enhancers
2014-12-15 | E-GEOD-64188 | biostudies-arrayexpress
Project description:Background: Signaling by receptor tyrosine kinases (RTK) is frequently dysregulated in gliomas. Inter-individual variability in the causes for dysregulated RTK signaling may have hampered the efficacy of targeted therapies. Using gene expression modules around key regulators in the RAS-RAF-MEK-MAPK cascade and in the phosphatidylinositol 3-kinase-AKT pathways, we developed a “RMPA” clustering scheme to distinguish gliomas with varying extents of RTK signaling. Results: We identified gene modules consistently co-expressed with NF1 (NF1-M), Sprouty (SPRY-M) and PTEN (PTEN-M) in gliomas. Their signatures enabled robust clustering of adult diffuse gliomas of WHO grades II-IV into RMPAhigh and RMPAlow phenotypes in a morphology-independent manner. In five independent data sets from three continents containing more than 1500 adult diffuse gliomas, RMPAhigh gliomas were associated with poor prognosis while RMPAlow gliomas were not. The RMPAhigh and RMPAlow glioma subtypes showed distinct levels of the activities of RAS-RAF-MEK-MAPK cascade and PI3K-AKT pathway and harbored unique sets of genomic alterations in the RTK signaling-related genes. The RMPAhigh gliomas contained large numbers of immature vessel cells and tumor associated macrophages and both cell types expressed high levels of pro-angiogenic RTKs including MET, VEGFR1, KDR, EPHB4 and NRP1. Conclusion: Inter-glioma variability in RTK signaling activities can be defined using the RMPA clustering scheme. The combined signatures of NF1-M, SPRY-M and PTEN-M reflect RTK signaling activity both in the glioma cells and in the glioma microenvironment. Our data show that RTK signaling in the glioma microenvironment may play a pivotal role in glioma progression.
2015-10-30 | GSE74462 | GEO