P53 regulates the conserved zebrafish microRNA-34 gene family, of which miR-34a has direct and p53-mediated effects including tumour suppression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA847446 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19594528.fastq.gz | Fastqsanger.gz | |||
| SRR19594529.fastq.gz | Fastqsanger.gz | |||
| SRR19594530.fastq.gz | Fastqsanger.gz | |||
| SRR19594531.fastq.gz | Fastqsanger.gz | |||
| SRR19594532.fastq.gz | Fastqsanger.gz |
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Project description:MiR-34a and miR-34b/c encoding genes represent direct targets of the p53 tumor suppressor. MiR-34a/b/c mediate tumor suppression by p53 via down-regulation of the expression of specific target mRNAs. Here, we characterized the miR-34 effectors using a CRISPR/Cas9-approach in HCT116 cells with or without 5-FU treatment.
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2022-06-14 | GSE205755 | GEO
Project description:Li-Fraumeni syndrome (LFS) is a disorder due to inherited mutations in the TP53 gene resulting in an increased risk of developing several types of cancer. MicroRNA miR-34a has been implicated downstream of p53 on the basis of being a direct transcriptional target and, when over-expressed, having pro-apoptotic phenotypes in cell lines. Moreover, miR-34a has been shown to be a modifier gene in the context of LFS, since its epigenetic silencing increases the likelihood of tumour development in patients with mutant TP53. However, the in vivo consequences of miR-34 loss are still unclear. For example, mice lacking all three (a,b,c) miR-34 homologs show no detectable abnormalities in p53 responses. The relative expression of different miR-34 genes in zebrafish was studied using qRT-PCR with specific assays. The miR-34a, miR-34b and miR-34c display unique onset of developmental expression and expression levels, with miR-34a being the most abundant and constant in expression. All of the miR-34 genes also showed clear induction by p53 when DNA-damaging treatments are performed. Using CRISPR-Cas9 technology, we generated a zebrafish miR-34a deletion mutant to further investigate the roles of miR-34a on its own and its association with the p53 pathway. Predictably, a miR-34a deletion mutant demonstrated absence of miR-34a, though without miR-34b and miR-34c compensation beyond baseline expression levels. Mutants survive to adulthood, show no overt phenotypes and have normal apoptotic responses to DNA-damaging irradiation or camptothecin treatments. To further explore the effects of miR-34a, we performed gene expression profiling using RNA-seq of wild-type and miR-34a deletion mutant zebrafish embryos at 72 hpf. We wanted to explore how miR-34a loss affects differentiated organs in larval zebrafish. This resulted in 389 genes UP and 374 genes DOWN at 1.5-fold change and FDR < 0.05. There was no significant enrichment of predicted miR-34a target genes among the differentially regulated genes but some interesting biological trends were found and will be described in the paper associated with this dataset.
2022-06-14 | GSE205754 | GEO
Project description:Li-Fraumeni syndrome (LFS) is a disorder due to inherited mutations in the TP53 gene resulting in an increased risk of developing several types of cancer. MicroRNA miR-34a has been implicated downstream of p53 on the basis of being a direct transcriptional target and, when over-expressed, having pro-apoptotic phenotypes in cell lines. Moreover, miR-34a has been shown to be a modifier gene in the context of LFS, since its epigenetic silencing increases the likelihood of tumour development in patients with mutant TP53. However, the in vivo consequences of miR-34 loss are still unclear. For example, mice lacking all three (a,b,c) miR-34 homologs show no detectable abnormalities in p53 responses. The relative expression of different miR-34 genes in zebrafish was studied using qRT-PCR with specific assays. The miR-34a, miR-34b and miR-34c display unique onset of developmental expression and expression levels, with miR-34a being the most abundant and constant in expression. All of the miR-34 genes also showed clear induction by p53 when DNA-damaging treatments are performed. Using CRISPR-Cas9 technology, we generated a zebrafish miR-34a deletion mutant to further investigate the roles of miR-34a on its own and its association with the p53 pathway. Predictably, a miR-34a deletion mutant demonstrated absence of miR-34a, though without miR-34b and miR-34c compensation beyond baseline expression levels. Mutants survive to adulthood, show no overt phenotypes and have normal apoptotic responses to DNA-damaging irradiation or camptothecin treatments. To further explore the effects of miR-34a, we performed gene expression profiling using RNA-seq of wild-type and miR-34a deletion mutant zebrafish embryos at 8 hpf. This experiment was motivated by a previous report knock-down of miR-34a in zebrafish leads to dramatic increases in expression of miR-34a target genes. We therefore expected that this experiment will help define the set of miR-34a target genes. The results of this RNA-seq experiment showed that the loss of miR-34a led to large transcriptomic effects at 8 hpf (1573 genes UP and 1679 genes DOWN at 1.5-fold change and FDR < 0.05). There was no significant enrichment of predicted miR-34a target genes among the differentially regulated genes but some interesting biological trends were found and will be described in the paper associated with this dataset.
2022-06-14 | GSE205752 | GEO
Project description:Li-Fraumeni syndrome (LFS) is a disorder due to inherited mutations in the TP53 gene resulting in an increased risk of developing several types of cancer. MicroRNA miR-34a has been implicated downstream of p53 on the basis of being a direct transcriptional target and, when over-expressed, having pro-apoptotic phenotypes in cell lines. Moreover, miR-34a has been shown to be a modifier gene in the context of LFS, since its epigenetic silencing increases the likelihood of tumour development in patients with mutant TP53. However, the in vivo consequences of miR-34 loss are still unclear. For example, mice lacking all three (a,b,c) miR-34 homologs show no detectable abnormalities in p53 responses. The relative expression of different miR-34 genes in zebrafish was studied using qRT-PCR with specific assays. The miR-34a, miR-34b and miR-34c display unique onset of developmental expression and expression levels, with miR-34a being the most abundant and constant in expression. All of the miR-34 genes also showed clear induction by p53 when DNA-damaging treatments are performed. Using CRISPR-Cas9 technology, we generated a zebrafish miR-34a deletion mutant to further investigate the roles of miR-34a on its own and its association with the p53 pathway. Predictably, a miR-34a deletion mutant demonstrated absence of miR-34a, though without miR-34b and miR-34c compensation beyond baseline expression levels. Mutants survive to adulthood, show no overt phenotypes and have normal apoptotic responses to DNA-damaging irradiation or camptothecin treatments. To further explore the effects of miR-34a, we performed gene expression profiling using RNA-seq of wild-type and miR-34a deletion mutant zebrafish embryos at 28 hpf with or without treatment with a DNA-damaging drug camptothecin. The results of this RNA-seq experiments showed that the loss of miR-34a does not strongly affect induction of genes by DNA-damage. However, the overall pattern of gene expression is significantly different as shown by Principal Component Analysis and there is a group of about 100 genes which are differentially expressed due to loss of miR-34a. The dataset we present in this submission was used to reach these conclusions.
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Project description:The miR-34 is a tumor-suppressor miRNA family involved in various human cancers, including breast. However, the role of such miRNAs in the control of mammary stem cells (MaSCs), early-progenitors and their tumor counterparts, (CSCs) lies largely unexplored. Here, we identified miR-34a as directly regulated by TP53 in primary mouse mammospheres. Expression of miR-34a is induced upon luminal commitment and differentiation and able to inhibit the expansion of the MaSCs/early-progenitor pool in a p53-independent fashion. Loss of function approaches revealed that miR-34 negatively controls both proliferation and fate commitment in mammary progenitors by modulating several pathways involved in epithelial cell plasticity and luminal-to-basal conversion. In particular, miR-34a negatively regulates Wnt/b-catenin signaling pathway, targeting multiple upstream regulators and, thus, modulating the expansion of the MaSCs/early-progenitor pool. These multiple roles of miR-34a were maintained in a model of human breast cancer, where chronic expression of miR-34a in triple-negative mesenchymal-like cells (enriched in CSCs) reduced tumor growth, restricted CSC pool and inhibited tumor propagation by promoting a luminal-like differentiation program.
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Project description:Analysis NCI-H1299 lung cancer cells transfected with synthetic oligo mimics for microRNAs (miRNAs) miR-34a and ghR-34a. We developed a 30-nucleotide single-strand RNA (ssRNA), termed “guide hairpin RNA (ghR),” that has a physiological function similar to that of miRNA and siRNA. The ghR caused no innate cytokine response either in vitro or in vivo. In addition, its structure does not contain a passenger strand seed sequence, reducing the potential for off-target effects relative to existing short RNA reagents. Systemic injection of ghR-form miR-34a (ghR-34a) suppressed tumor growth in a mouse model of RAS-induced lung cancer. Furthermore, ghR-34a functioned in a Dicer- and Ago2-independent manner. This novel RNAi technology may provide a novel, safe, and effective nucleic acid drug platform that will increase the clinical usefulness of nucleic acid therapy. MiR-34a–targeted mRNAs regulated by mRNA degradation rather than translational inhibition were identified using microarray data from miR-34 and ghR-34a transfectants.
2015-07-29 | E-GEOD-71423 | biostudies-arrayexpress
Project description:The miR-34 family of microRNAs consisting of miR-34a, miR-34b and miR-34c are tumour suppressors. The annotated human miR-34b-5p has one additional base at the 5’ end of the common miR-34 family seed sequence, compared to miR-34a-5p and miR-34c-5p. This extra base results in a shift of the seed sequence, which would affect the target gene repertoire and have functional consequences. During our studies of miR-34 functions, we investigated the precise sequence of mature miR-34b-5p in human cells by deep sequencing. We found that a miR-34b-5p without the extra base was the predominant form in both non-malignant and malignant cells derived from several human tissues, indicating that the miR-34b annotation is misleading. We evaluated the functional implications of the seed shift, by comparing the effect of mimics representing the alternative miR-34b-5p sequences in MDA-MB-231 cells. In contrast to the annotated miR-34b, the endogenously expressed miR-34b displayed tumour suppressive characteristics in vitro similarly to miR-34c. These data demonstrate the importance of determining the precise sequence of a mature microRNA before exploring miRNA functions.
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Project description:Expression of the miR-34 family (miR-34a, -34b, -34c) is elevated in settings of heart disease, and inhibition with antimiR-34a/antimiR-34 has emerged as a promising therapeutic strategy. Under chronic cardiac disease settings, targeting the entire miR-34 family is more effective than targeting miR-34a alone. The identification of transcription factor (TF)-miRNA regulatory networks has added complexity to understanding the therapeutic potential miRNA-based therapies. Here, we sought to determine whether antimiR-34 targets secondary miRNAs via TFs which could contribute to antimiR-34-mediated protection. Using miRNA-Seq we identified differentially regulated miRNAs in hearts from mice with cardiac pathology due to transverse aortic constriction (TAC), and these miRNAs were also regulated by antimiR-34. Two clusters of stress-responsive miRNAs were classified as “pathological” and “cardioprotective”. Using ChIPBase we identified 45 TF binding sites on the promoters of “pathological” and “cardioprotective” miRNAs, and 5 represented direct targets of miR-34, with the capacity to regulate other miRNAs. The expression of two “pathological” miRNAs (let-7e and miR-31) was independently experimentally validated in hearts from antimiR-34 treated TAC mice, and may explain why targeting the entire miR-34 family is more effective than targeting miR-34a alone. AntimiR-34 regulates the expression of other miRNAs and this has significant implications for drug development.
2016-05-08 | GSE79050 | GEO