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MicroRNA-203 represses selection and expansion of oncogenic HRas transformed tumor initiating cells [seq]

ABSTRACT: In many mouse models of skin cancer, only a few tumors typically form although many cells competent for tumorigenesis receive the same oncogenic mutations. These observations suggest a selection process for defining tumor initiating cells. Here we use quantitative mRNA- and miR-Seq to determine the impact of HRasG12V on the transcriptome of keratinocytes. We discover that microRNA-203 is downregulated by HRasG12V. Using a knockout mouse model, we demonstrate that loss of microRNA-203 promotes selection and expansion of tumor-initiating cells. Conversely, restoration of microRNA-203 with an inducible model potently inhibits proliferation of these cells. We comprehensively identify microRNA-203 targets required for HRas-initiated tumorigenesis. These targets include important effectors of the Ras pathway and essential genes required for cell division. Together, this study establishes a role for the loss of microRNA-203 in promoting selection and expansion of HRas mutated cells and identifies a mechanism through which microRNA-203 antagonizes HRas-mediated tumorigenesis. Identifying mRNA and microRNA networks regulated by oncogenic HRasG12V in primary keratinocytes through the use of 3Seq and small-RNA-Sequencing. Additionally we utilize ribosome-profiling, 3Seq, Microarray and Ago2-HITS-CLIP approaches to identify novel miR-203 target genes.

ORGANISM(S): Mus musculus

SUBMITTER: Kent Riemondy

PROVIDER: E-GEOD-66054 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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MicroRNA-203 represses selection and expansion of oncogenic HRas transformed tumor initiating cells [array]

Project description:In many mouse models of skin cancer, only a few tumors typically form although many cells competent for tumorigenesis receive the same oncogenic mutations. These observations suggest a selection process for defining tumor initiating cells. Here we use quantitative mRNA- and miR-Seq to determine the impact of HRasG12V on the transcriptome of keratinocytes. We discover that microRNA-203 is downregulated by HRasG12V. Using a knockout mouse model, we demonstrate that loss of microRNA-203 promotes selection and expansion of tumor-initiating cells. Conversely, restoration of microRNA-203 with an inducible model potently inhibits proliferation of these cells. We comprehensively identify microRNA-203 targets required for HRas-initiated tumorigenesis. These targets include important effectors of the Ras pathway and essential genes required for cell division. Together, this study establishes a role for the loss of microRNA-203 in promoting selection and expansion of HRas mutated cells and identifies a mechanism through which microRNA-203 antagonizes HRas-mediated tumorigenesis. Identifying mRNA and microRNA networks regulated by oncogenic HRasG12V in primary keratinocytes through the use of 3Seq and small-RNA-Sequencing. Additionally we utilize ribosome-profiling, 3Seq, Microarray and Ago2-HITS-CLIP approaches to identify novel miR-203 target genes.

2015-07-23 | E-GEOD-66055 | biostudies-arrayexpress

MicroRNA-203 represses selection and expansion of oncogenic HRas transformed tumor initiating cells [array]

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MicroRNA-203 represses selection and expansion of oncogenic HRas transformed tumor initiating cells [seq]

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Quantitative polyadenylation map of mouse embryonic epidermal lineages

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Project description:MicroRNA-203 represses selection and expansion of oncogenic HRas transformed tumor initiating cells

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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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Project description:MicroRNA-203 represses selection and expansion of oncogenic HRas transformed tumor initiating cells [array]

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