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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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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]

2015-07-23 | GSE66055 | GEO

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

2015-07-23 | GSE66054 | GEO

Quantitative polyadenylation map of mouse embryonic epidermal lineages

Project description:We establish an experimental and bioinformatic pipeline using 3SEQ to quantitatively measure mRNA expression and reliably determine 3' end formation by sequencing polyadenylated transcripts. When applied to purified mouse embryonic skin stem cells direct differentiation lineages, we identify 15,651 UTRs representing 10,442 distinct mRNAs that are abundantly expressed in the skin. We determine that ~80% of UTRs are formed by using canonical A[A/U]UAAA polyadenylation signals, whereas ~20% of UTRs utilize alternative signals. We demonstrate that comparing with qPCR, our RNA-Seq approach can precisely measure mRNA fold-change and accurately determine the expression of mRNAs over four orders of magnitude. We also reported 453 out of 10,442 genes (4.3%) show differential 3' end usage between skin stem cells and their direct differentiation lineages. Among them, core components of the miRNA pathway, including Dicer, Dgcr8, Xpo5 and Ago2, show dynamic 3' UTR formation patterns, indicating a self-regulatory mechanism. Together, our quantitative analysis reveals a dynamic picture of mRNA 3' end formation in closely related somatic stem cell lineages. Perform 3SEQ in E14 epidermal basal cells and E14 epidermal suprabasal cells.

2013-01-01 | E-GEOD-37641 | biostudies-arrayexpress

Oncogenic Hras-dependent epidermal growth is inhibited following RNAi-mediated depletion of Ctnnb1 and Mllt6

Project description:Genome-wide RNAi screens in mice identified Ctnnb1 and Mllt6 as physiological regulators of HrasG12V-dependent epidermal hyperplasia. To probe the consequences of Ctnnb1 and Mllt6 on HrasG12V-dependent oncogenic growth, we examined how their depletion impacts gene expression in the HrasoncoX2 epidermis. We performed RNA-seq analysis of FACS-purified embryonic epidermal cells, followed by network analysis of differentially regulated transcripts. Whether Ctnnb1 or Mllt6, knockdown markedly enhanced activity of genes restricting growth, and decreased expression of genes promoting epidermal proliferation. This contrasted with known transcriptional changes that typically follow epidermal expression of oncogenic Hras. Moreover, there was a significant overlap in genes whose expression was affected by Mllt6 and β-catenin, further implying a level of shared function. Transcriptional profiles of epidermal progenitors of embryonic day 18.5 animals of wild-type, HrasG12V, and HrasG12V depleted of Ctnnb1 or Mllt6 backgrounds.

2013-07-03 | E-GEOD-48480 | biostudies-arrayexpress

The miRNA expression signature of human MALT lymphoma

Project description:To identify key tumour supressor miRNAs involed in MALT lymphoma pathogenesis Gastric mucosa-associated lymphoid tissue lymphoma develops in the chronically inflamed mucosa of Helicobacter pylori-infected patients. MicroRNA expression profiling of human MALT lymphoma revealed a 10-fold down-regulation of miR-203, which resulted from promoter hypermethylation and coincided with the dysregulation of the miR-203 target ABL1. Demethylating treatment of lymphoma B-cells led to an increase in miR-203 expression and concomitant ABL1 down-regulation. The lentiviral delivery of miR-203, as well as treatment with various ABL inhibitors, prevented primary MALT lymphoma cell proliferation in vitro. Finally, the treatment of tumor-bearing mice with imatinib induced MALT lymphoma regression in vivo. Our results show that MALT lymphomagenesis is epigenetically induced by miR-203 promoter methylation and identify ABL1 as a novel target for the treatment of this malignancy. 5 human fresh frozen MALT lymphoma samples were analysed and 4 human tonsil tissue samples were used as the non-tumour control

2010-08-31 | E-GEOD-23877 | biostudies-arrayexpress

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

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

| PRJNA275785 | ENA

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.

2015-08-22 | E-GEOD-64190 | biostudies-arrayexpress

Gene expression of wild-type and Ppar-beta null primary keratinocytes, with and without infection with an activated Hras retrovirus, with and without the Ppar-beta specific ligand GW0742

Project description:Differential gene expression profiles were observed in response to Hras in either wild-type or Ppar-beta null primary keratinocytes and differentail gene edxpression profiles by GW0742 were only found in wild-type keratinocytes. Primary keratinocytes from wild-type and Ppar-beta null mice were either mock infected or infected with an Hras encoding retrovirus and treated with or without 1 uM GW0742 for 24 hours.

2012-04-11 | E-GEOD-32498 | biostudies-arrayexpress

RNA-seq of IL-4 stimulated human keratinocytes

Project description:In this study we aim to determine the role of IL-4/STAT6 in gene expression in human keratinocytes using RNA-sequencing approach. Human keratinocytes were cultured for 2 or 5 days with calcium chloride to induce terminal differentiation as determined by the expression of epidermal differentiation complex genes. The cells were then stimulated with IL-4 for 3 and 24 hours, or along the 5 days culture period. We observed that IL-4 inhibits fully differentiation of keratinocytes, induces genes involved with production of inflammatory mediators, and reduces the healing capacity of human keratinocytes. Moreover, STAT6 controlled important genes involved with calcium binding, inflammation and epidermis development. Human keratinocytes were differentiated with calcium chloride for 2 days and incubated with media alone or 20ng/ml of recombinant human IL-4 for 3 and 24 hours. Human keratinocytes were differentiated with calcium chloride for 5 days with or wihout recombinant human IL-4 (20ng/ml). Keratinocytes transfected with control or STAT6 siRNA were differentiated with calcium chloride for 2 days and then stimulated with recombinant huma IL-4 for 24 hours.

2015-12-15 | E-GEOD-59275 | biostudies-arrayexpress

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