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A latent pro-survival function for the mir-290-295 cluster in mouse embryonic stem cells.

ABSTRACT: MicroRNAs (miRNAs) post-transcriptionally regulate the expression of thousands of distinct mRNAs. While some regulatory interactions help to maintain basal cellular functions, others are likely relevant in more specific settings, such as response to stress. Here we describe such a role for the mir-290-295 cluster, the dominant miRNA cluster in mouse embryonic stem cells (mESCs). Examination of a target list generated from bioinformatic prediction, as well as expression data following miRNA loss, revealed strong enrichment for apoptotic regulators, two of which we validated directly: Caspase 2, the most highly conserved mammalian caspase, and Ei24, a p53 transcriptional target. Consistent with these predictions, mESCs lacking miRNAs were more likely to initiate apoptosis following genotoxic exposure to gamma irradiation or doxorubicin. Knockdown of either candidate partially rescued this pro-apoptotic phenotype, as did transfection of members of the mir-290-295 cluster. These findings were recapitulated in a specific mir-290-295 deletion line, confirming that they reflect miRNA functions at physiological levels. In contrast to the basal regulatory roles previously identified, the pro-survival phenotype shown here may be most relevant to stressful gestations, where pro-oxidant metabolic states induce DNA damage. Similarly, this cluster may mediate chemotherapeutic resistance in a neoplastic context, making it a useful clinical target. Three replicates of mouse embryonic stem cells with Dicer (CTRL) compared to three replicates of mouse embryonic stem cells lacking Dicer (CRE)

ORGANISM(S): Mus musculus

SUBMITTER: Charles Whittaker

PROVIDER: E-GEOD-30012 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A latent pro-survival function for the mir-290-295 cluster in mouse embryonic stem cells.

Project description:MicroRNAs (miRNAs) post-transcriptionally regulate the expression of thousands of distinct mRNAs. While some regulatory interactions help to maintain basal cellular functions, others are likely relevant in more specific settings, such as response to stress. Here we describe such a role for the mir-290-295 cluster, the dominant miRNA cluster in mouse embryonic stem cells (mESCs). Examination of a target list generated from bioinformatic prediction, as well as expression data following miRNA loss, revealed strong enrichment for apoptotic regulators, two of which we validated directly: Caspase 2, the most highly conserved mammalian caspase, and Ei24, a p53 transcriptional target. Consistent with these predictions, mESCs lacking miRNAs were more likely to initiate apoptosis following genotoxic exposure to gamma irradiation or doxorubicin. Knockdown of either candidate partially rescued this pro-apoptotic phenotype, as did transfection of members of the mir-290-295 cluster. These findings were recapitulated in a specific mir-290-295 deletion line, confirming that they reflect miRNA functions at physiological levels. In contrast to the basal regulatory roles previously identified, the pro-survival phenotype shown here may be most relevant to stressful gestations, where pro-oxidant metabolic states induce DNA damage. Similarly, this cluster may mediate chemotherapeutic resistance in a neoplastic context, making it a useful clinical target.

2011-06-18 | GSE30012 | GEO

Transcriptomes of miR-290-295 KO mESCs treated with siPOOLs for three different transcription factors and a negative control

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mRNA expression analysis of undifferentiated Dicer -/- (27H10) embryonic stem cells after miRNA transfection

Project description:We have analyzed the transcript expression levels in Dicer knock-out embryonic stem (ES) cells 24 hours after transfection with either control siRNA agains Renilla luciferase or miRNA Mimics (Dharmacon) of mmu-miR-290 cluster members in order to identify primary targets of miR-290 cluster miRNAs. Keywords: Comparison of effect of two different transfections on transcriptome of Dicer-KO ES cells

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Transcriptomes of miR-290-295 KO mESCs treated with siPOOLs against the transcription factor Tfap4

Project description:In order to identify direct microRNA targets in mouse embryonic stem cells (mESCs), we knocked out microRNA effector genes, profiled their transcriptomes and integrated the data with additional published OMICs data sets. To validate the analysis, we generated miR-290-295 KO mutant cell lines, assessed the transcriptome profile and compared the observed misregulation to the predictions of the analysis. We identified the transcription factor Tfap4 as novel potential direct and functional target of miR-290-295. To assess the role of Tfap4, we rescued its expression in the miR-290-295 KO cell line using siPOOLs and profiled the transcriptome.

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Transcriptome of miR-290-295 KO mESCs

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A biogenesis step upstream of Microprocessor controls miR-17~92 expression

Project description:The precise control of miR-17~92 microRNA (miRNA) is essential for normal development and overexpression of certain miRNAs from this cluster is oncogenic. Here we find the relative expression of the six miRNAs processed from the primary (pri-miR-17~92) transcript is dynamically regulated during embryonic stem cell differentiation. We identify a new miRNA biogenesis intermediate, termed ‘progenitor-miRNA’ (pro-miRNA), that is an efficient substrate for Microprocessor. An autoinhibitory 5’ RNA fragment is cleaved to generate pro-miRNA and selectively license Microprocessor-mediated production of pre-miR-17, -18a, -19a, 20a, and -19b. Using genetic, biochemical, and structural methods we define two complementary cis-regulatory repression domains required for the formation of this inhibitory RNA conformation. We find the endonuclease CPSF3 (CPSF73), and the Spliceosome-associated ISY1 are required for pro-miRNA biogenesis and expression of all miRNAs within the cluster except miR-92. Thus, developmentally regulated generation of pro-miRNA explains the posttranscriptional control of miR-17~92 expression in development. Illumina RNAseq in WT, dgcr8-/- and dicer-/- mESCs and small RNA seq in WT mESCs

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2008-06-16 | E-GEOD-8503 | biostudies-arrayexpress

Transcriptome of miR-290-295 KO mESCs

2022-07-15 | GSE179450 | GEO

Mus musculus

Project description:A latent pro-survival function for the mir-290-295 cluster in mouse embryonic stem cells.

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Transcription profiling of mouse Dicer-null cell lines vs. wt ES cells and Dicer-null cell lines vs. Dicer-null cells overexpressing Dnmt1 or Dnmt3a/3b

Project description:Dicer initiates RNA interference by generating small RNAs involved in various silencing pathways. Dicer participates in centromeric silencing, but its role in the epigenetic regulation of other chromatin domains has not been explored. Here we show that Dicer1 deficiency in Mus musculus leads to decreased DNA methylation, concomitant with increased telomere recombination and telomere elongation. These DNA-methylation defects correlate with decreased expression of Dnmt1, Dnmt3a and Dnmt3b DNA methyltransferases (Dnmts), and methylation levels can be recovered by their overexpression. We identify the retinoblastoma-like 2 protein (Rbl2) as responsible for decreased Dnmt expression in Dicer1-null cells, suggesting the existence of Dicer-dependent small RNAs that target Rbl2. We identify the miR-290 cluster as being downregulated in Dicer1-deficient cells and show that it silences Rbl2, thereby controlling Dnmt expression. These results identify a pathway by which miR-290 directly regulates Rbl2-dependent Dnmt expression, indirectly affecting telomere-length homeostasis. Experiment Overall Design: Two-condition experiments. 6 comparisons. One dye-swap technical replicate for all samples. 2-color platform.

2008-06-19 | E-GEOD-11229 | biostudies-arrayexpress

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