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Concurrent Disruption of Ras-Erk and NF-κB Pathways Induces Circadian Deregulation and Hepatocarcinogenesis

ABSTRACT: Mice with hepatocyte-specific deletion of both Shp2 and IkkB were generated, which disrupted basal levels of Ras-ERK and NF-kB signaling. These mice exhibited accelerated liver tumor formation compared to either single knockout alone. RNA-Seq analysis of whole liver and isolated hepatocytes from all genotypes were performed to identify tumor-promoting factors in the DKO model. Along with inflammatory and

ORGANISM(S): Mus musculus

PROVIDER: GSE158381 | GEO | 2021/12/01

REPOSITORIES: GEO

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Concurrent Disruption of Ras-Erk and NF-κB Pathways Induces Circadian Deregulation and Hepatocarcinogenesis

Project description:Concurrent Disruption of Ras-Erk and NF-κB Pathways Induces Circadian Deregulation and Hepatocarcinogenesis

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

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-08-22 | E-GEOD-64195 | biostudies-arrayexpress

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

Project description:This SuperSeries is composed of the SubSeries listed below.

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SHP2 Drives Adaptive Resistance to ERK Signaling Inhibition in Molecularly Defined Subsets of ERK-dependent Tumors

Project description:We performed RNA sequencing analysis using NextSeq500 to identify drivers that mediate feedback RAS activation in BRAF(V600E) cells that are SHP2 independent.

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Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape [RNA-seq]

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.

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Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape [ChIP-seq]

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.

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Let-7a regulates mammosphere formation capacity through Ras/NF-κB and Ras/MAPK/ERK pathway in breast cancer stem cells.

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