Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA388478 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5629400.fastq.gz | Fastqsanger.gz | |||
| SRR5629401.fastq.gz | Fastqsanger.gz | |||
| SRR5629402.fastq.gz | Fastqsanger.gz | |||
| SRR5629403.fastq.gz | Fastqsanger.gz | |||
| SRR5629404.fastq.gz | Fastqsanger.gz |
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Project description:Previous studies have evaluated the role of miRNAs in the initiation and progression of cancer. MiR-34a was found to be downregulated in several tumors, including medulloblastoma. We here analysed the function of miR-34a in vivo by targeted transgenesis to generate mice with constitutive deletion of the miR-34a gene, which resulted in the absence of mir-34a in all analysed tissues. Nevertheless, these mice were viable and fertile. A comprehensive standardized phenotypic analysis including more than 300 single parameters performed by the German Mouse Clinic revealed no apparent phenotype. Analysis of miR-34a expression in human medulloblastomas and medulloblastoma cell lines revealed significant downregulation as compared to human cerebellum. Re-expression of mir-34a in human medulloblastoma cells in vitro reduced cell viability, cell proliferation and induced apoptosis. Among the targets downregulated by miR-34a in human medulloblastoma cells were NMYC and SIRT1. Activation of the Shh pathway by targeted overexpression of SmoA1 causes medulloblastoma in mice, which is dependent on the presence and upregulation of NMYC. Analysis of miR-34a in ND2:SmoA1-derived medulloblastomas revealed significant suppression of miR-34a compared to normal cerebellum. Crossbreeding these mice with miR-34a knockout mice significantly accelerated medulloblastoma growth in mice deficient for miR-34a. Interestingly, NMYC and SIRT1 were highly expressed in medulloblastomas derived from these mice. We here demonstrate that miR-34a is dispensable for normal development, but that its loss accelerates medulloblastoma. Strategies aiming to re-express miR-34a in tumors could therefore represent an efficient therapy option.
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Project description:We determined the effect of p53 activation on de novo protein synthesis using quantitative proteomics of newly synthesized proteins (pulsed stable isotope labeling with amino acids in cell culture, pSILAC) in combination with mRNA and non-coding RNA expression analyses by next generation sequencing (RNA-, miR-Seq) in the colorectal cancer (CRC) cell line SW480. Furthermore, genome-wide DNA binding of p53 was analyzed by chromatin-immunoprecipitation (ChIP-Seq). Thereby, we identified differentially regulated mRNAs (1258 up, 415 down), miRNAs (111 up, 95 down), lncRNAs (270 up, 123 down) and proteins (542 up, 569 down). Changes in mRNA and protein expression levels showed a positive correlation (r = 0.50, p < 0.0001). More transcriptionally induced genes displayed occupied p53 binding sites (4.3% mRNAs, 7.2% miRNAs, 6.3% lncRNAs, 5.9% proteins) than repressed genes (2.4% mRNAs, 3.2% miRNAs, 0.8% lncRNAs, 1.9% proteins), suggesting indirect mechanisms of repression. Around 50% of the downregulated proteins displayed seed-matching sequences of p53-induced miRNAs in the corresponding 3’-UTRs. Moreover, proteins repressed by p53 significantly overlapped with those previously shown to be repressed by miR-34a. We confirmed upregulation of the novel direct p53 target genes LINC01021, MDFI, ST14 and miR-486 and showed that ectopic LINC01021 expression inhibited proliferation in SW480 cells. Furthermore, HMGB1, KLF12 and CIT mRNAs were confirmed as direct targets of the p53-induced miR-34a, miR-205 and miR-486-5p, respectively. In line with the loss of p53 function during tumor progression, elevated expression of HMGB1, KLF12 and CIT was detected in advanced stages of cancer. This study provides new insights and a comprehensive catalogue of p53-mediated regulations and p53 DNA binding in CRC cells.
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Project description:Previous studies have evaluated the role of miRNAs in the initiation and progression of cancer. MiR-34a was found to be downregulated in several tumors, including medulloblastoma. We here analysed the function of miR-34a in vivo by targeted transgenesis to generate mice with constitutive deletion of the miR-34a gene, which resulted in the absence of mir-34a in all analysed tissues. Nevertheless, these mice were viable and fertile. A comprehensive standardized phenotypic analysis including more than 300 single parameters performed by the German Mouse Clinic revealed no apparent phenotype. Analysis of miR-34a expression in human medulloblastomas and medulloblastoma cell lines revealed significant downregulation as compared to human cerebellum. Re-expression of mir-34a in human medulloblastoma cells in vitro reduced cell viability, cell proliferation and induced apoptosis. Among the targets downregulated by miR-34a in human medulloblastoma cells were NMYC and SIRT1. Activation of the Shh pathway by targeted overexpression of SmoA1 causes medulloblastoma in mice, which is dependent on the presence and upregulation of NMYC. Analysis of miR-34a in ND2:SmoA1-derived medulloblastomas revealed significant suppression of miR-34a compared to normal cerebellum. Crossbreeding these mice with miR-34a knockout mice significantly accelerated medulloblastoma growth in mice deficient for miR-34a. Interestingly, NMYC and SIRT1 were highly expressed in medulloblastomas derived from these mice. We here demonstrate that miR-34a is dispensable for normal development, but that its loss accelerates medulloblastoma. Strategies aiming to re-express miR-34a in tumors could therefore represent an efficient therapy option. For genome-wide expression analysis total RNA from brain and thymus of three or four male miR34a and four control mice was isolated using RNeasy Midi kit (Qiagen, Hilden, Germany). The cDNA microarrays were generated, hybridized and analysed as described (Horsch et al 2009). Two chip hybridizations were performed with total RNA for each individual mutant mouse against a reference RNA pool of the same organ.
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