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IGF2 mRNA binding protein 3 (IMP3) mediated regulation of transcriptome and translatome in glioma cells.

ABSTRACT: RNA binding proteins mediate global regulation at the level of transcriptome and translatome of a cell. We studied the global level expression changes regulated by IMP3 in transcriptome and translatome by performing microarray using total cellular RNA and heavy polysome derived RNA of IMP3 silenced glioma cells respectively. Differentially regulated transcripts at the transcriptome level (n = 2388) and at the level of translatome (n = 479) were identified. Further, these transcripts were classified as direct and indirect targets on the basis of presence of IMP3 binding site. Additional investigation revealed that direct targets at transcriptome level were found to be associated with processes related to cell cycle, whereas direct targets at the translatome level participated in apoptosis related pathways. Probable mechanism of indirect regulation at both the levels is also investigated. Collectively, our study reveals multi-level gene expression regulation imposed by IMP3 in glioma cells.

SUBMITTER: Bhargava S

PROVIDER: S-EPMC5790340 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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IGF2 mRNA binding protein 3 (IMP3) mediated regulation of transcriptome and translatome in glioma cells.

Bhargava Shruti S Patil Vikas V Shah Riyaz Ahmad RA Somasundaram Kumaravel K

Cancer biology & therapy 20171219 1

RNA binding proteins mediate global regulation at the level of transcriptome and translatome of a cell. We studied the global level expression changes regulated by IMP3 in transcriptome and translatome by performing microarray using total cellular RNA and heavy polysome derived RNA of IMP3 silenced glioma cells respectively. Differentially regulated transcripts at the transcriptome level (n = 2388) and at the level of translatome (n = 479) were identified. Further, these transcripts were classif ...[more]

PMID: 28485999

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Project description:The insulin-like growth factor 2 (IGF2) mRNA binding proteins (IMPs/IGF2BPs) IMP1 and 3 are regarded as oncofetal proteins, whereas the hepatic IMP2 expression in adults is controversially discussed. The splice variant IMP2-2/p62 promotes steatohepatitis and hepatocellular carcinoma. Aim of this study was to clarify whether IMP2 is expressed in the adult liver and influences progression toward cirrhosis. IMP2 was expressed at higher levels in embryonic compared to adult tissues as quantified in embryonic, newborn, and adult C57BL/6J mouse livers and suggested by analysis of publicly available human data. In an IMP2-2 transgenic mouse model microarray and qPCR analyses revealed increased expression of liver progenitor cell (LPC) markers Bex1, Prom1, Spp1, and Cdh1 indicating a de-differentiated liver cell phenotype. Induction of these LPC markers was confirmed in human cirrhotic tissue datasets. The LPC marker SPP1 has been described to play a major role in fibrogenesis. Thus, DNA methylation was investigated in order to decipher the regulatory mechanism of Spp1 induction. In IMP2-2 transgenic mouse livers single CpG sites were differentially methylated, as quantified by amplicon sequencing, whereas human HCC samples of a human publicly available dataset showed promoter hypomethylation. In order to study the impact of IMP2 on fibrogenesis in the context of steatohepatitis wild-type or IMP2-2 transgenic mice were fed either a methionine-choline deficient (MCD) or a control diet for 2-12 weeks. MCD-fed IMP2-2 transgenic mice showed a higher incidence of ductular reaction (DR), accompanied by hepatic stellate cell activation, extracellular matrix (ECM) deposition, and induction of the LPC markers Spp1, Cdh1, and Afp suggesting the occurrence of de-differentiated cells in transgenic livers. In human cirrhotic samples IMP2 overexpression correlated with LPC marker and ECM component expression. Progression of liver disease was induced by combined MCD and diethylnitrosamine (DEN) treatment. Combined MCD-DEN treatment resulted in shorter survival of IMP2-2 transgenic compared to wild-type mice. Only IMP2-2 transgenic livers progressed to cirrhosis, which was accompanied by strong DR. In conclusion, IMP2 is an oncofetal protein in the liver that promotes DR characterized by de-differentiated cells toward steatohepatitis-associated cirrhosis development with poor survival.

Dataset Information

IGF2 mRNA binding protein 3 (IMP3) mediated regulation of transcriptome and translatome in glioma cells.

Publications

IGF2 mRNA binding protein 3 (IMP3) mediated regulation of transcriptome and translatome in glioma cells.

Similar Datasets

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