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RNA-sequencing in OS-RC-2 cells under the knockdown of Arkadia or ESRP2

ABSTRACT: Tumor-specific alternative splicing is implicated in the progression of cancer, including clear cell renal cell carcinoma (ccRCC). Using ccRCC RNA-sequencing data from The Cancer Genome Atlas, we found that epithelial splicing regulatory protein 2 (ESRP2), one of the key regulators of alternative splicing in epithelial cells, is expressed in ccRCC. ESRP2 mRNA expression did not correlate with the overall survival rate of ccRCC patients, but the expression of some ESRP-target exons correlated with the good prognosis and with the expression of Arkadia (also known as RNF111) in ccRCC. Arkadia physically interacted with ESRP2, induced polyubiquitination, and modulated its splicing function. Arkadia and ESRP2 suppressed ccRCC tumor growth in a coordinated manner. Lower expression of Arkadia correlated with advanced tumor stages and poor outcomes in ccRCC patients. This study thus reveals a novel tumor-suppressive role of the Arkadia-ESRP2 axis in ccRCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE66741 | GEO | 2015/08/01

SECONDARY ACCESSION(S): PRJNA277837

REPOSITORIES: GEO

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RNA-sequencing in OS-RC-2 cells under the knockdown of Arkadia or ESRP2

Project description:Tumor-specific alternative splicing is implicated in the progression of cancer, including clear cell renal cell carcinoma (ccRCC). Using ccRCC RNA-sequencing data from The Cancer Genome Atlas, we found that epithelial splicing regulatory protein 2 (ESRP2), one of the key regulators of alternative splicing in epithelial cells, is expressed in ccRCC. ESRP2 mRNA expression did not correlate with the overall survival rate of ccRCC patients, but the expression of some ESRP-target exons correlated with the good prognosis and with the expression of Arkadia (also known as RNF111) in ccRCC. Arkadia physically interacted with ESRP2, induced polyubiquitination, and modulated its splicing function. Arkadia and ESRP2 suppressed ccRCC tumor growth in a coordinated manner. Lower expression of Arkadia correlated with advanced tumor stages and poor outcomes in ccRCC patients. This study thus reveals a novel tumor-suppressive role of the Arkadia-ESRP2 axis in ccRCC. Expression of mRNA in a ccRCC cell line OS-RC-2 under the knockdown of Arkadia or ESRP2. Knock-down of ESRP2 was confirmed by RT-PCR because of low expression of ESRP2 which resulted in non-quantitative FPKM value.

2015-08-01 | E-GEOD-66741 | biostudies-arrayexpress

The epithelial splicing factors ESRP1 and ESRP2 positively and negatively regulate alternative splicing events

Project description:Epithelial Splicing Regulatory Proteins 1 and 2 (ESRP1 and ESRP2) are recently discovered epithelial-specific RNA-binding proteins that promote splicing of the epithelial variant of the FGFR2, ENAH, CD44, and CTNND1 transcripts. To catalogue a larger set of splicing events under the regulation of the ESRPs, we profiled splicing changes induced by RNA interference-mediated knockdown of ESRP1 and ESRP2 expression in a human epithelial cell line using the splicing-sensitive Affymetrix Exon ST1.0 Arrays. Analysis of the microarray data using the previously described MADS tool resulted in the identification of over a hundred candidate ESRP-regulated splicing events. We were able to independently validate 37 of these targets by RT-PCR. The ESRP-regulated events encompass all known types of alternative splicing events. Importantly, a number of these regulated splicing events occur in gene transcripts that encode proteins with well-described roles in the regulation of actin cytoskeleton organization, cell-cell adhesion, cell polarity, and cell migration. In sum, this work reveals a novel list of transcripts differentially spliced in epithelial and mesenchymal cells, implying that coordinated alternative splicing plays a critical role in determination of cell type identity. Keywords: control / knockdown comparison Short interfering knockdown of ESRP1 and ESRP2 in human PNT2 prostatic epithelium cells was performed as described before (Warzecha et al., 2009, Molecular Cell 33:591-601). The efficiency of ESRP1 and ESRP2 knockdown was monitored by quantitative RT-PCR as described before (Warzecha et al., 2009, Molecular Cell 33:591-601). In all cases the efficiency of the knockdown was close to 80%. We conducted Exon array profiling on RNAs from four siESRP1/2-treated samples and four siGFP controls.

2010-08-18 | E-GEOD-17468 | biostudies-arrayexpress

The epithelial splicing factors ESRP1 and ESRP2 positively and negatively regulate alternative splicing events

2009-08-15 | GSE17468 | GEO

Modulation of ESRP2 and MBNL2 in normal kidney and clear cell renal cell carcinoma cell lines for analysis of stability programs

Project description:While analyzing mRNA expression profiles of clear cell renal cell carcinoma (ccRCC) tumors, we found that the mRNAs that are bound at their 3' UTRs by muscleblind-like splicing regulator 2 (Mbnl2) and epithelial splicing regulatory protein 2 (ESRP2) are up-regulated in tumor compared to patient-matched normal tissues. Given that MBNL2 increases the stability of its targets and ESRP2 destabilizes its targets, we predicted that, in ccRCC tumors, MBNL2 activity increases, while ESRP2 activity decreases. To investigate the effect of each of these two RNA-binding proteins (RBPs) on the transcriptome of the cell, we used shRNA to knockdown MBNL2 in two different cell line models of ccRCC (786-O and A-498), and also to knockdown ESRP2 in normal primary renal proximal tubule epithelial cells (PRPTEC). RNA-seq revealed that MBNL2 knockdown partially reverses the ccRCC-associated transcriptome in ccRCC cell lines, whereas ESRP2 knockdown shifts the transcriptome of PRPTEC toward that of ccRCC.

2018-03-23 | GSE83999 | GEO

Knockout mice reveal an essential role for Epithelial splicing regulatory proteins (Esrps) in mammalian development and epithelial splicing in vivo

Project description:Tissue- and cell-type specific regulators of alternative splicing (AS) are an essential layer of posttranscriptional gene regulation necessary for normal cellular function, patterning, and development. Here we report the Epithelial splicing regulatory proteins (Esrps) are required for patterning of multiple organs, with loss of both paralogs, Esrp1 and Esrp2, resulting in increasingly severe phenotypes. Global profiling of the Esrp splicing regulatory network from total epidermis revealed varied splicing sensitivity of Esrp targets upon loss of Esrp1 or double knockout. This may explain the progressive phenotypes seen in Esrp knockout mice, and these mice provide a unique genetic tool to evaluate functional consequences of epithelial splicing events in vivo. RNA from purified total epidermis (basal keratinocyte layer to cornified layer) of E18.5 mouse embryos were harvested by Trizol extraction. (Esrp1+/+, Esrp2-/- (n=2), Esrp1-/-, Esrp2+/+ (n=3), Esrp1-/-, Esrp2+/- (n=2), and Esrp1-/-, Esrp2-/- (n=2). 1 ug of total RNA was used for for RNA-seq library preparation using the TruSeq™ Stranded mRNA LT Sample Prep Kit (Illumina). 100x2 bp paired-end RNA-seq reads were generated on a HiSeq 2000 sequencer.

2015-09-08 | E-GEOD-64357 | biostudies-arrayexpress

ESRP2 Regulates A Conserved And Cell-Type-Specific Splicing Program to Support Postnatal Liver Maturation

Project description:Alternative splicing greatly expands the proteomic diversity but its functional impact is often unclear. Here, we identify a highly conserved and temporally coordinated cell-type-specific splicing program, which is activated in part by ESRP2 during postnatal liver development. Consistent with failure of many neonatal-to-adult splicing transitions, Esrp2 null mice exhibit persistent expression of fetal markers and loss of mature hepatocyte characteristics. Conversely, ectopic expression of ESRP2 in immature mouse or human hepatocytes results in a reciprocal switch in splicing. Our findings define an essential role for ESRP2 in generation of conserved repertoires of adult splice isoforms that facilitate postnatal liver maturation. Mouse liver RNA was isolated with Trizol (Invitrogen). Hi-Seq libraries were prepared and paired-end 100bp Illumina sequencing was performed on mouse liver samples from different developmental stages.

2015-11-04 | E-GEOD-67009 | biostudies-arrayexpress

ESRP2 Regulates A Conserved And Cell-Type-Specific Splicing Program to Support Postnatal Liver Maturation

2015-11-04 | GSE67009 | GEO

Knockout mice reveal an essential role for Epithelial splicing regulatory proteins (Esrps) in mammalian development and epithelial splicing in vivo

2015-09-08 | GSE64357 | GEO

An ESRP-regulated splicing program is abrogated during the Epithelial Mesenchymal Transition

Project description:Alternative splicing achieves coordinated changes in post-transcriptional gene expression programs through the activities of diverse RNA binding proteins. Epithelial Splicing Regulatory Proteins 1 and 2 (ESRP1 and ESRP2) are cell type-specific regulators of transcripts that switch splicing during the Epithelial Mesenchymal Transition (EMT). To define a comprehensive program of alternative splicing that is regulated during the EMT, we identified an extensive ESRP-regulated splicing network of hundreds of alternative splicing events within numerous genes with roles in cell-cell adhesion, polarity, and migration. Loss of this global ESRP-regulated epithelial splicing program induces the phenotypic changes in cell morphology that are observed during the EMT. Components of this splicing signature provide novel molecular markers that can be used to characterize the EMT. Bioinformatics and experimental approaches revealed a high affinity ESRP binding motif and a predictive RNA map that governs their activity. This work establishes the ESRPs as coordinators of a complex alternative splicing network that adds an important post-transcriptional layer to the changes in gene expression that underlie epithelial-mesenchymal transitions during development and disease. Keywords: control / knockdown comparison and control / ectopic expression comparison

2010-08-23 | GSE22937 | GEO

RNA-sequencing of neutrophils derived from OS-RC-2-bearing mice

Project description:Advanced clear cell renal cell carcinoma (ccRCC) frequently causes systemic inflammation. Here, we identified the functional role and regulatory mechanism of inflammation driven by advanced ccRCC cells. The inflammatory nature of advanced ccRCC was recapitulated in a preclinical model of ccRCC. Amplification of cancer cell-intrinsic inflammation during ccRCC progression triggered neutrophil-dependent lung metastasis. Massive expression of inflammation-related genes was transcriptionally activated by epigenetic remodelling through mechanisms such as DNA demethylation and super-enhancer formation. Bromodomain and extra-terminal motif inhibitor (BETi) synchronously suppressed C–X–C-type chemokines in ccRCC cells and decreased neutrophil-dependent lung metastasis. Overall, our findings shed insight into the nature of inflammatory ccRCC, which triggers metastatic cascades, and suggest a potential therapeutic strategy.

2020-10-28 | GSE131138 | GEO

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