title: Extensive microRNA-mediated crosstalk between lncRNAs and mRNAs in mouse embryonic stem cells.
abstract: Recently, a handful of intergenic long noncoding RNAs (lncRNAs) have been shown to compete with mRNAs for binding to miRNAs and to contribute to development and disease. Beyond these reports, little is yet known of the extent and functional consequences of miRNA-mediated regulation of mRNA levels by lncRNAs. To gain further insight into lncRNA-mRNA miRNA-mediated crosstalk, we reanalyzed transcriptome-wide changes induced by the targeted knockdown of over 100 lncRNA transcripts in mouse embryonic stem cells (mESCs). We predicted that, on average, almost one-fifth of the transcript level changes induced by lncRNAs are dependent on miRNAs that are highly abundant in mESCs. We validated these findings experimentally by temporally profiling transcriptome-wide changes in gene expression following the loss of miRNA biogenesis in mESCs. Following the depletion of miRNAs, we found that >50% of lncRNAs and their miRNA-dependent mRNA targets were up-regulated coordinately, consistent with their interaction being miRNA-mediated. These lncRNAs are preferentially located in the cytoplasm, and the response elements for miRNAs they share with their targets have been preserved in mammals by purifying selection. Lastly, miRNA-dependent mRNA targets of each lncRNA tended to share common biological functions. Post-transcriptional miRNA-mediated crosstalk between lncRNAs and mRNA, in mESCs, is thus surprisingly prevalent, conserved in mammals, and likely to contribute to critical developmental processes.
authors: MRC Functional Genomics Unit, University of Oxford, Oxford OX1 3QX, United Kingdom; University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford OX1 3QX, United Kingdom; Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland;
authors: Jennifer Y
authors: JY
authors: Tan
authors: MRC Functional Genomics Unit, University of Oxford, Oxford OX1 3QX, United Kingdom; University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford OX1 3QX, United Kingdom;
authors: Tamara
authors: T
authors: Sirey
authors: MRC Functional Genomics Unit, University of Oxford, Oxford OX1 3QX, United Kingdom; University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford OX1 3QX, United Kingdom; Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland;
authors: Frantisek
authors: F
authors: Honti
authors: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford OX3 9DS, United Kingdom; Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, United Kingdom;
authors: Bryony
authors: B
authors: Graham
authors: Department of Experimental, Diagnostic and Specialty Medicine (DIMES),Unit of Histology, Embryology and Applied Biology, University of Bologna, 40126 Bologna, BO, Italy.
authors: Allison
authors: A
authors: Piovesan
authors: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, United Kingdom;
authors: Matthias
authors: M
authors: Merkenschlager
authors: MRC Functional Genomics Unit, University of Oxford, Oxford OX1 3QX, United Kingdom; University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford OX1 3QX, United Kingdom;
authors: Caleb
authors: C
authors: Webber
authors: MRC Functional Genomics Unit, University of Oxford, Oxford OX1 3QX, United Kingdom; University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford OX1 3QX, United Kingdom;
authors: Chris P
authors: CP
authors: Ponting
authors: MRC Functional Genomics Unit, University of Oxford, Oxford OX1 3QX, United Kingdom; University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford OX1 3QX, United Kingdom; Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland;
authors: Ana C
authors: AC
authors: Marques
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D012323:RNA Processing, Post-Transcriptional; D062085:RNA, Long Noncoding / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D059467:Transcriptome
chemical_list: D035683:MicroRNAs; D062085:RNA, Long Noncoding; D012333:RNA, Messenger