Cytosine methylation of mature microRNAs inhibits their functions and is associated with poor prognosis in glioblastoma multiforme
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina HiSeq 1500
ORGANISM(S): Homo sapiens
SUBMITTER: Amandine Etcheverry
PROVIDER: E-MTAB-7684 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:As early as one month of age, non-obese diabetic (NOD) mice feature pancreatic infiltration of autoreactive T lymphocytes, which destruct insulin-producing beta cells, leading to autoimmune diabetes mellitus (T1D) within eight months. Thus, we hypothesized that during the development of T1D, the transcriptional modulation of immune reactivity genes, as well as, modulation of microRNAs (miRNAs) may occur during thymocytes mature into peripheral CD3+ T lymphocytes. Our aim is to analyze the transcriptional modulation of mRNA and microRNAs during development of thymocytes into peripheral CD3+ T lymphocytes in the context of the emergence of T1D.
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Project description:MicroRNAs (miRNAs) are a family of short, noncoding RNAs that regulate translation of mRNAs by mechanisms involving the binding of complementary sequences. The influence of miRNAs on the proteome and cellular events is extensive as they regulate an estimated 60% of the transcriptome and play key roles in differentiation, plasticity, circadian rhythm, immunity, and disease. The post-transcriptional biogenesis of most miRNAs involves a sequential cleavage process mediated by RNase III family enzymes. Primary transcripts (pri-miRNAs) are first cleaved by Drosha in the nucleus to yield ~70nt hairpin precursors (pre-miRNAs). These intermediates are transported to the cytoplasm where ~22mer dsRNAs are excised by Dicer. Typically, one strand of the dsRNAs is inserted as a mature miRNA into the RNA-induced silencing complex (RISC), which contains members of the Argonaute (Ago) protein family that contribute to translational regulation. Recent studies indicate that some RNA-binding proteins (RNA-BPs) can regulate discrete processing steps, differentially blocking or promoting the formation of specific miRNAs to control cellular proliferation and differentiation. Elegant examples of this mechanism include the attenuation of let-7 biogenesis in embryonic stem cells by the pluripotency factor LIN28, and the selective enhancement of miR-18a biogenesis from a polycistronic transcript by hnRNPA1. Mature miRNA expression profiles in B104 cells were measured after siRNA-mediated knockdown of RBM3 in the B104 neuronal cell line. Mock treated B104 cells were used as a control. Experiments were replicated in duplicates.
2011-11-10 | E-GEOD-33519 | biostudies-arrayexpress
Project description:Non-obese diabetic (NOD) mice feature pancreatic infiltration of autoreactive T lymphocytes as early as 1 month of age, which destruct insulin-producing beta-cells to finally emerge autoimmune diabetes mellitus (T1D) within 8 months. In view, we hypothesized that during the development of T1D, transcriptional modulation of immune reactivity genes may occur as thymocytes mature toward peripheral T lymphocytes. Transcriptome of thymocytes and peripheral CD3+ T lymphocytes from pre-diabetic or diabetic mice analyzed through microarray hybridizations allowed observation of 3,586 differentially expressed genes. Hierarchical clustering grouped mice according to age/T1D onset and genes to their ontology. Transcriptional activity of thymocytes toward peripheral T lymphocytes unraveled sequential participation of genes involved with CD4+/CD8+ T cell differentiation (Themis), tolerance induction (Foxp3), apoptosis (Fasl) to soon after T cell activation (IL4), while the emergence of T1D coincided with the expression of cytotoxicity (Crtam) and inflammatory response genes (Tlr) by peripheral T lymphocytes.
2011-03-03 | E-MEXP-3047 | biostudies-arrayexpress
Project description:DNA methylation stabilizes developmentally programmed gene expression states. Aberrant methylation is associated with disease progression and is a common feature of cancer genomes. Presently, few methods enable quantitative, large-scale, single-base resolution mapping of DNA methylation states in desired regions of a complex mammalian genome. Here, we present an approach that combines array-based hybrid selection and massively parallel bisulfite sequencing to profile DNA methylation in genomic regions spanning hundreds of thousands of bases. This single molecule strategy enables methylation variable positions to be quantitatively examined with high sampling precision. Using bisulfite capture, we assessed methylation patterns across 324 randomly selected CpG islands (CGI) representing more than 25,000 CpG sites. A single lane of Illumina sequencing permitted methylation states to be definitively called for >90% of target sties. The accuracy of the hybrid-selection approach was verified using conventional bisulfite capillary sequencing of cloned PCR products amplified from a subset of the selected regions. This confirmed that even partially methylated states could be successfully called. A comparison of human primary and cancer cells revealed multiple differentially methylated regions. More than 25% of islands showed complex methylation patterns either with partial methylation states defining the entire CGI or with contrasting methylation states appearing in specific regional blocks within the island. We observed that transitions in methylation state often correlate with genomic landmarks, including transcriptional start sites and intron-exon junctions. Methylation, along with specific histone marks, was enriched in exonic regions, suggesting that chromatin states can foreshadow the content of mature mRNAs. Keywords: DNA methylation profiling by massively parallel sequencing Keywords: Epigenetics Targeted examination of DNA methylation in two human cell types by combining array capture and bisulfite sequencing. In addition, this study examined two histone marks in the breast tumor cell line MDA-MB-231.
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Project description:Cerebral Aneurysm tissues and superficial temporal arteries were compared through RNA-Seq to identify differentially expressed genes, and through microRNA microarray to identify differentially expressed microRNAs. Significant miR:gene pairs were identified for potential microRNA silencing regualtory effects. To study differentially expressed genes and microRNAs in cerebral aneurysms, we collected 7 cerebral aneurysm tisses and 10 superficial temporal artery (STA) tisses from 17 individuals. We performed RNA-Seq and microRNA microarray analysis on these samples, and compared them using STA as a control.
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Project description:BackgroundLiterature reports that mature microRNA (miRNA) can be methylated at adenosine, guanosine and cytosine. However, the molecular mechanisms involved in cytosine methylation of miRNAs have not yet been fully elucidated. Here we investigated the biological role and underlying mechanism of cytosine methylation in miRNAs in glioblastoma multiforme (GBM).MethodsRNA immunoprecipitation with the anti-5methylcytosine (5mC) antibody followed by Array, ELISA, dot blot, incorporation of a radio-labelled methyl group in miRNA, and miRNA bisulfite sequencing were perfomred to detect the cytosine methylation in mature miRNA. Cross-Linking immunoprecipiation qPCR, transfection with methylation/unmethylated mimic miRNA, luciferase promoter reporter plasmid, Biotin-tagged 3'UTR/mRNA or miRNA experiments and in vivo assays were used to investigate the role of methylated miRNAs. Finally, the prognostic value of methylated miRNAs was analyzed in a cohorte of GBM pateints.ResultsOur study reveals that a significant fraction of miRNAs contains 5mC. Cellular experiments show that DNMT3A/AGO4 methylated miRNAs at cytosine residues inhibit the formation of miRNA/mRNA duplex and leading to the loss of their repressive function towards gene expression. In vivo experiments show that cytosine-methylation of miRNA abolishes the tumor suppressor function of miRNA-181a-5p miRNA for example. Our study also reveals that cytosine-methylation of miRNA-181a-5p results is associated a poor prognosis in GBM patients.ConclusionTogether, our results indicate that the DNMT3A/AGO4-mediated cytosine methylation of miRNA negatively.
| S-EPMC7041276 | biostudies-literature
Project description:This SuperSeries is composed of the following subset Series: GSE22141: MicroRNA signature during the time course of regeneration of the human airway mucociliary epithelium GSE22142: Transcriptome analysis during the time course of regeneration of the human airway mucociliary epithelium GSE22143: Transcriptomic impact of microRNAs-449 or microRNAs-34 overexpression in proliferating human airway epithelial cells GSE22144: miRNAs high throughput sequencing profiling of regenerating human airway epithelial cells GSE22145: miRNAs high throughput sequencing profiling of basals cells and columnar cells GSE22146: microRNAs signatures of Xenopus laevis embryo epidermis at stage 11 (non ciliated) and 26 (ciliated) using high throughput sequencing Refer to individual Series
2011-06-06 | E-GEOD-22147 | biostudies-arrayexpress
Project description:One goal of viral infection is to reprogram the host cell to optimize viral replication. As part of this process, viral miRNAs may compete for components of the miRNA/siRNA pathway as well as regulate cellular targets. Mouse Cytomegalovirus has been described to generate large numbers of viral miRNAs during lytic infection and was therefore used to analyze the impact of viral miRNAs on the host cell small RNA system as well as to check for sorting of viral small RNAs into specific Ago-proteins. Deep sequencing analysis of MCMV infected cells revealed that viral miRNAs represent only app. 13% of all detected miRNAs. All previously described MCMV miRNAs with the exception of miR-m88-1* were confirmed and for the MCMV miR-m01-1 hairpin an additional miRNA, designated miR-m01-1-3p, was found. Its presence was confirmed by qPCR and Northern Blot. Deep sequencing after RISC IP with antibodies specific for either Ago1 or Ago2 showed that all MCMV miRNAs are loaded into both RISC complexes. The ratio of MCMV to mouse miRNAs was not increased after immunoprecipitation of Ago-proteins. Viral miRNAs therefore do not overwhelm the host miRNA processing system nor are they preferentially incorporated into RISC. We found that 3 mouse miRNAs showed an altered expression due to MCMV infection. Down-regulation of miR-27a, as previously described, could be confirmed. In addition, miR-26a was down-regulated and an up-regulation of miR-7a dependent on viral protein expression could be observed. Examination of small RNA expression in uninfected vs. infected cells, immunoprecipitation + sequencing of Ago1 and Ago2 loaded small RNAs in infected cells
2012-06-30 | E-GEOD-36919 | biostudies-arrayexpress
Project description:Cytosine methylation of mature microRNAs inhibits their functions and is associated with poor prognosis in glioblastoma multiforme
| PRJEB31319 | ENA