title: Transcriptome dynamics of the microRNA inhibition response.
abstract: We report a high-resolution time series study of transcriptome dynamics following antimiR-mediated inhibition of miR-9 in a Hodgkin lymphoma cell-line-the first such dynamic study of the microRNA inhibition response-revealing both general and specific aspects of the physiological response. We show miR-9 inhibition inducing a multiphasic transcriptome response, with a direct target perturbation before 4 h, earlier than previously reported, amplified by a downstream peak at ∼32 h consistent with an indirect response due to secondary coherent regulation. Predictive modelling indicates a major role for miR-9 in post-transcriptional control of RNA processing and RNA binding protein regulation. Cluster analysis identifies multiple co-regulated gene regulatory modules. Functionally, we observe a shift over time from mRNA processing at early time points to translation at later time points. We validate the key observations with independent time series qPCR and we experimentally validate key predicted miR-9 targets. Methodologically, we developed sensitive functional data analytic predictive methods to analyse the weak response inherent in microRNA inhibition experiments. The methods of this study will be applicable to similar high-resolution time series transcriptome analyses and provides the context for more accurate experimental design and interpretation of future microRNA inhibition studies.
authors.affiliation: The Bioinformatics Centre, Department of Biology, University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen N, Denmark Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen N, Denmark.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Wen
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen N, Denmark Laboratory for Molecular Cancer Biology, Center for the Biology of Disease, VIB, 3000 Leuven, Belgium; Laboratory for Molecular Cancer Biology, Center of Human Genetics, VIB, 3000 Leuven, Belgium.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Leucci
authors.affiliation: Laboratory for Molecular Cancer Biology, Center for the Biology of Disease, VIB, 3000 Leuven, Belgium; Laboratory for Molecular Cancer Biology, Center of Human Genetics, VIB, 3000 Leuven, Belgium.
authors.forename: Roberto
authors.initials: R
authors.lastname: Vendramin
authors.affiliation: Department of Haematology, Aalborg University Hospital, A.C. Meyers Vnge 15, 2450 Copenhagen SV, Denmark.
authors.forename: Sakari
authors.initials: S
authors.lastname: Kauppinen
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen N, Denmark anders.lund@bric.ku.dk.
authors.forename: Anders H
authors.initials: AH
authors.lastname: Lund
authors.affiliation: The Bioinformatics Centre, Department of Biology, University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen N, Denmark krogh@binf.ku.dk.
authors.forename: Anders
authors.initials: A
authors.lastname: Krogh
authors.affiliation: The Bioinformatics Centre, Department of Biology, University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen N, Denmark Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis street, #07-01, Singapore 138671 bparker@binf.ku.dk.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Parker
mesh_terms: D045744:Cell Line, Tumor; D016000:Cluster Analysis; D005786:Gene Expression Regulation; D023281:Genomics; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors*; D008957:Models, Genetic; D012323:RNA Processing, Post-Transcriptional; D016601:RNA-Binding Proteins / Q000378:metabolism; D059467:Transcriptome
chemical_list: D035683:MicroRNAs; D016601:RNA-Binding Proteins