Dataset Information

Identification of functional miRNA gene interactions in mESC by computational data integration approaches.

ABSTRACT: miRNAs are short regulatory single stranded RNA sequences that upon complementary binding to mRNAs lead to the inhibition or degradation of their targets. This regulatory mechanisms has been shown to play crucial roles throughout the whole life cycle of animals and plants as well as in disease. While a plethora of methods exist to predict targets of miRNA, which suggest that up to 80% of the genome is miRNA regulated, it has recently been reported that many of these predictions are false positives, cell type specific or represent non-functional binding. In order to identify the subset of real functional miRNAs and their targets, we established miRNA pathway mutants in mouse embryonic stem cells (mESC), allowing the dissection of canonical and non-canonical functions of pathway members. Additional data integration of downstream regulatory layers (CLIP-seq, ribosome profiling and MS) enabled us to follow and track down real functional miRNA-gene interactions, which reduced the miRNA genome regulation to approximately 1%.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Embryo, Endosperm, Embryonic Stem Cell

SUBMITTER: Tatjana Sajic

LAB HEAD: Prof. Dr. Rudolf Aebersold

PROVIDER: PXD014484 | Pride | 2022-08-31

REPOSITORIES: Pride

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Publications

Global and precise identification of functional miRNA targets in mESCs by integrative analysis.

Schaefer Moritz M Nabih Amena A Spies Daniel D Hermes Victoria V Bodak Maxime M Wischnewski Harry H Stalder Patrick P Ngondo Richard Patryk RP Liechti Luz Angelica LA Sajic Tatjana T Aebersold Ruedi R Gatfield David D Ciaudo Constance C

EMBO reports 20220728 9

MicroRNA (miRNA) loaded Argonaute (AGO) complexes regulate gene expression via direct base pairing with their mRNA targets. Previous works suggest that up to 60% of mammalian transcripts might be subject to miRNA-mediated regulation, but it remains largely unknown which fraction of these interactions are functional in a specific cellular context. Here, we integrate transcriptome data from a set of miRNA-depleted mouse embryonic stem cell (mESC) lines with published miRNA interaction predictions ...[more]

PMID: 35899551

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Project description:Schmitz2014 - RNA triplex formation The model is parameterized using the parameters for gene CCDC3 from Supplementary Table S1. The two miRNAs which form the triplex together with CCDC3 are miR-551b and miR-138. This model is described in the article: Cooperative gene regulation by microRNA pairs and their identification using a computational workflow. Schmitz U, Lai X, Winter F, Wolkenhauer O, Vera J, Gupta SK. Nucleic Acids Res. 2014 Jul; 42(12): 7539-7552 Abstract: MicroRNAs (miRNAs) are an integral part of gene regulation at the post-transcriptional level. Recently, it has been shown that pairs of miRNAs can repress the translation of a target mRNA in a cooperative manner, which leads to an enhanced effectiveness and specificity in target repression. However, it remains unclear which miRNA pairs can synergize and which genes are target of cooperative miRNA regulation. In this paper, we present a computational workflow for the prediction and analysis of cooperating miRNAs and their mutual target genes, which we refer to as RNA triplexes. The workflow integrates methods of miRNA target prediction; triplex structure analysis; molecular dynamics simulations and mathematical modeling for a reliable prediction of functional RNA triplexes and target repression efficiency. In a case study we analyzed the human genome and identified several thousand targets of cooperative gene regulation. Our results suggest that miRNA cooperativity is a frequent mechanism for an enhanced target repression by pairs of miRNAs facilitating distinctive and fine-tuned target gene expression patterns. Human RNA triplexes predicted and characterized in this study are organized in a web resource at www.sbi.uni-rostock.de/triplexrna/. This model is hosted on BioModels Database and identified by: BIOMD0000000530. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Background: The differential expression pattern of microRNAs (miRNAs) during mammary gland development might provide insights into their role in regulating the homeostasis of the breast epithelium. Our aim was to analyse these regulatory functions by deriving a comprehensive tissue-specific combined miRNA and mRNA expression profile of post-natal mouse mammary gland development. We measured the expression of 318 individual murine miRNAs by bead-based flow-cytometric profiling of whole mouse mammary glands throughout a 16-point developmental time course, including juvenile, puberty, mature virgin, gestation, lactation, and involution stages. In parallel whole-genome mRNA expression data were obtained. Results: One third (n = 102) of all murine miRNAs analysed were present during mammary gland development. MicroRNAs were represented in seven temporally co-expressed clusters, which were enriched for both miRNAs belonging to the same family and breast cancer-associated miRNAs. Global miRNA and mRNA expression was significantly reduced during lactation and the early stages of involution after weaning. For most detected miRNA families we did not observe systematic changes in the expression of predicted targets. For miRNA families whose targets did show significant changes, we observed inverse patterns of miRNA and target expression. The datasets are made publicly available and the combined expression profiles represent an important community resource for mammary gland biology research. Conclusions: MicroRNAs were expressed in co-regulated clusters during mammary gland development. Breast cancer-associated miRNAs were significantly enriched in these clusters. The mechanism and functional consequences of this miRNA co-regulation and its correlation with mRNA expression provide new avenues for research into mammary gland biology and generates candidates for functional validation. Developmental time course over 16 time points with 1-3 independent biological replicates per time point and three pairs of technical replicates, 40 samples in total

Project description:Background: The differential expression pattern of microRNAs (miRNAs) during mammary gland development might provide insights into their role in regulating the homeostasis of the breast epithelium. Our aim was to analyse these regulatory functions by deriving a comprehensive tissue-specific combined miRNA and mRNA expression profile of post-natal mouse mammary gland development. We measured the expression of 318 individual murine miRNAs by bead-based flow-cytometric profiling of whole mouse mammary glands throughout a 16-point developmental time course, including juvenile, puberty, mature virgin, gestation, lactation, and involution stages. In parallel whole-genome mRNA expression data were obtained. Results: One third (n = 102) of all murine miRNAs analysed were present during mammary gland development. MicroRNAs were represented in seven temporally co-expressed clusters, which were enriched for both miRNAs belonging to the same family and breast cancer-associated miRNAs. Global miRNA and mRNA expression was significantly reduced during lactation and the early stages of involution after weaning. For most detected miRNA families we did not observe systematic changes in the expression of predicted targets. For miRNA families whose targets did show significant changes, we observed inverse patterns of miRNA and target expression. The datasets are made publicly available and the combined expression profiles represent an important community resource for mammary gland biology research. Conclusions: MicroRNAs were expressed in co-regulated clusters during mammary gland development. Breast cancer-associated miRNAs were significantly enriched in these clusters. The mechanism and functional consequences of this miRNA co-regulation and its correlation with mRNA expression provide new avenues for research into mammary gland biology and generates candidates for functional validation. This SuperSeries is composed of the following subset Series: GSE15054: Characterisation of microRNA expression in post-natal mouse mammary gland development [gene] GSE15055: Characterisation of microRNA expression in post-natal mouse mammary gland development [miRNA] Refer to individual Series

Dataset Information

Identification of functional miRNA gene interactions in mESC by computational data integration approaches.

Publications

Global and precise identification of functional miRNA targets in mESCs by integrative analysis.

Similar Datasets

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