Modulation of microRNA processing by 5-lipoxygenase
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE152901 | GEO | 2020/10/30
REPOSITORIES: GEO
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Project description:Human 5-lipoxygenase (5-LO) is the key enzyme of leukotriene biosynthesis, mostly expressed in leukocytes and thus a crucial component of the innate immune system. In this study, we show that 5-LO, beside its canonical function as a metabolizing enzyme, is also a regulator of gene expression in the monocytic cell line Mono Mac 6 (MM6). Using RNA-Seq, we identified 5-LO regulated genes which could be clustered to several biological functions, e.g. immune/defense response, cell adhesion, transcription and growth/developmental processes. Thereby, the majority of genes were upregulated by 5-LO KO. By conducting a ChIP-Seq analysis, we proved an association of 5-LO to DNA. In summary, we demonstrate an additional noncanonical function of 5-LO as a direct transcriptional regulator in MM6 cells that presumably regulates specific genes in dependence on histone acetylation.
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Project description:Human 5-lipoxygenase (5-LO) is the key enzyme of leukotriene biosynthesis, mostly expressed in leukocytes and thus a crucial component of the innate immune system. In this study, we show that 5-LO, beside its canonical function as a metabolizing enzyme, is also a regulator of gene expression in the monocytic cell line Mono Mac 6 (MM6). Using RNA-Seq, we identified 5-LO regulated genes which could be clustered to several biological functions, e.g. immune/defense response, cell adhesion, transcription and growth/developmental processes. Thereby, the majority of genes were upregulated by 5-LO KO. By conducting a ChIP-Seq analysis, we proved an association of 5-LO to DNA. In summary, we demonstrate an additional noncanonical function of 5-LO as a direct transcriptional regulator in MM6 cells that presumably regulates specific genes in dependence on histone acetylation.
2022-07-25 | GSE200332 | GEO
Project description:Human 5-lipoxygenase (5-LO) is the key enzyme of leukotriene biosynthesis, mostly expressed in leukocytes and thus a crucial component of the innate immune system. In this study, we show that 5-LO, beside its canonical function as a metabolizing enzyme, is also a regulator of gene expression in the monocytic cell line Mono Mac 6 (MM6). Using RNA-Seq, we identified 5-LO regulated genes which could be clustered to several biological functions, e.g. immune/defense response, cell adhesion, transcription and growth/developmental processes. Thereby, the majority of genes were upregulated by 5-LO KO. By conducting a ChIP-Seq analysis, we proved an association of 5-LO to DNA. In summary, we demonstrate an additional noncanonical function of 5-LO as a direct transcriptional regulator in MM6 cells that presumably regulates specific genes in dependence on histone acetylation.
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Project description:As the biogenesis of miRNAs depends on the cleavage by the RNase III enzyme Dicer, miR-18a may change the miRNA expression profiles by targeting dicer. We then performed the miRNA array assay to investigate the miRNA profiles change caused by miR-18a.
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Project description:As the biogenesis of miRNAs depends on the cleavage by the RNase III enzyme Dicer, miR-18a may change the miRNA expression profiles by targeting dicer. We then performed the miRNA array assay to investigate the miRNA profiles change caused by miR-18a. Total RNA obtained from two pairs,one is the miR-18a overexpression cell line compared to the miRNAs (control), the other is the over-expression miR-18a cell line transfected Dicer plasmid.
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Project description:MicroRNAs are small regulatory RNAs that post-transcriptionally control gene expression. Reduced expression of DICER, the enzyme involved in microRNA processing, is frequently observed in cancer and is associated with poor clinical outcome in various malignancies. Yet the underlying mechanisms are not well understood. Here, we identify tumor hypoxia as a regulator of DICER expression in large cohorts of breast cancer patients. We show that DICER expression is suppressed by hypoxia through an epigenetic mechanism that involves inhibition of oxygen-dependent H3K27me3 demethylases KDM6A/B and results in silencing of the DICER promoter. Subsequently, reduced miRNA processing leads to derepression of the miR-200 target ZEB1, stimulates the epithelial to mesenchymal transition and ultimately results in the acquisition of stem cell phenotypes in human mammary epithelial cells. Our study uncovers a previously unknown relationship between oxygen-sensitive epigenetic regulators, miRNA biogenesis and tumor stem cell phenotypes that may underlie poor outcome in breast cancer. miRNA profiling of MCF7 cells in normal or hypoxic conditions or after DICER knockdown in MCF7 cells.
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Project description:MicroRNAs influence hematopoietic differentiation, but little is known about their effects on the stem cell state. Here, we report that the microRNA processing enzyme Dicer is essential for stem cell persistence in vivo and a specific microRNA, miR-125a controls the size of the stem cell population by regulating stem/progenitor cell (HSPC) apoptosis. Conditional deletion of Dicer revealed an absolute dependence for the multipotent HSPC population in a cell autonomous manner, with increased HSPC apoptosis in mutant animals. An evolutionarily conserved microRNA cluster containing miR-99b, let-7e and miR-125a was preferentially expressed in long term HSCs. miR-125a alone was capable of increasing the number of hematopoietic stem cells in vivo by more than eight fold. This was accomplished through a differentiation stage-specific reduction of apoptosis in immature hematopoietic progenitors, possibly through targeting multiple pro-apoptotic genes. Bak1 was directly down-regulated by miR-125a and expression of a 3’UTR-less Bak1 blocked miR-125a-induced hematopoietic expansion in vivo. These data demonstrate cell-state-specific regulation by microRNA and identify a unique microRNA functioning to regulate the stem cell pool size.
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Project description:We have used genome editing to generate inactivating deletion mutations in all three copies of the dicer (hdcr) gene present in the human cell line 293T. As previously shown in murine ES cells lacking Dicer function, hDcr-deficient 293T cells are severely impaired for the production of mature microRNAs (miRNAs). Nevertheless, RNA-induced silencing complexes (RISCs) present in these hDcr-deficient cells are readily programmed by transfected, synthetic miRNA duplexes to repress mRNAs bearing either fully or partially complementary targets, including targets bearing incomplete seed homology to the introduced miRNA. Using these hDcr-deficient 293T cells, we demonstrate that human pre-miRNA processing can be effectively rescued by ectopic expression of the Drosophila Dicer 1 protein, but only in the presence of the PB isoform of Loquacious (Loqs-PB), the fly homolog of the hDcr co-factor TRBP. In contrast, Drosophila Dicer 2, even in the presence of its co-factors Loqs-PD and R2D2, was unable to support human pre-miRNA processing. Interestingly, although ectopic Drosophila Dicer 1/Loqs-PB or hDcr both rescued pre-miRNA processing effectively in these hDcr-deficient cells, there were significant differences in the ratio of the miRNA isoforms that were produced, especially in the case of miR-30 family members, and we also noted differences in the relative expression level of miRNAs versus passenger strands for a subset of human miRNAs. These data demonstrate that the mechanisms underlying the accurate processing of pre-miRNAs are largely, but not entirely, conserved between mammalian and insect cells. Series includes three datasets of total small RNA reads from wild type and Dicer negative 293T cells. Also included are total small RNA reads of the Dicer-negative cell line NoDice(4-25) transfected with a vector expressing human Dicer, Drosophila Dicer1, or mock transfected. RISC-associated small RNAs identified by ribonucleoprotein immunoprecipitation (RIP-Seq) in wild type 293T, Dicer-negative NoDice(4-25) line, and NoDice(4-25) transfected with either hsa-miR-155 or kshv-miR-K12-11 miRNA duplexes. The final data series are PAR-CLIP libraries which identified microRNA targets in untransfected NoDice(4-25) cells and NoDice(4-25) cells transfected with either hsa-miR-92a, hsa-miR-155, kshv-miR-K12-11 miRNA duplexes
2014-04-17 | E-GEOD-56836 | biostudies-arrayexpress
Project description:MicroRNAs are small regulatory RNAs that post-transcriptionally control gene expression. Reduced expression of DICER, the enzyme involved in microRNA processing, is frequently observed in cancer and is associated with poor clinical outcome in various malignancies. Yet the underlying mechanisms are not well understood. Here, we identify tumor hypoxia as a regulator of DICER expression in large cohorts of breast cancer patients. We show that DICER expression is suppressed by hypoxia through an epigenetic mechanism that involves inhibition of oxygen-dependent H3K27me3 demethylases KDM6A/B and results in silencing of the DICER promoter. Subsequently, reduced miRNA processing leads to derepression of the miR-200 target ZEB1, stimulates the epithelial to mesenchymal transition and ultimately results in the acquisition of stem cell phenotypes in human mammary epithelial cells. Our study uncovers a previously unknown relationship between oxygen-sensitive epigenetic regulators, miRNA biogenesis and tumor stem cell phenotypes that may underlie poor outcome in breast cancer. A total of 12 samples were analyzed. For each condition tested, 3 independent experiments were carried out (biological repicates).
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Project description:MicroRNAs are small regulatory RNAs that post-transcriptionally control gene expression. Reduced expression of DICER, the enzyme involved in microRNA processing, is frequently observed in cancer and is associated with poor clinical outcome in various malignancies. Yet the underlying mechanisms are not well understood. Here, we identify tumor hypoxia as a regulator of DICER expression in large cohorts of breast cancer patients. We show that DICER expression is suppressed by hypoxia through an epigenetic mechanism that involves inhibition of oxygen-dependent H3K27me3 demethylases KDM6A/B and results in silencing of the DICER promoter. Subsequently, reduced miRNA processing leads to derepression of the miR-200 target ZEB1, stimulates the epithelial to mesenchymal transition and ultimately results in the acquisition of stem cell phenotypes in human mammary epithelial cells. Our study uncovers a previously unknown relationship between oxygen-sensitive epigenetic regulators, miRNA biogenesis and tumor stem cell phenotypes that may underlie poor outcome in breast cancer.
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