title: Alternative polyadenylation allows differential negative feedback of human miRNA miR-579 on its host gene ZFR.
abstract: About half of the known miRNA genes are located within protein-coding host genes, and are thus subject to co-transcription. Accumulating data indicate that this coupling may be an intrinsic mechanism to directly regulate the host gene's expression, constituting a negative feedback loop. Inevitably, the cell requires a yet largely unknown repertoire of methods to regulate this control mechanism. We propose APA as one possible mechanism by which negative feedback of intronic miRNA on their host genes might be regulated. Using in-silico analyses, we found that host genes that contain seed matching sites for their intronic miRNAs yield longer 32UTRs with more polyadenylation sites. Additionally, the distribution of polyadenylation signals differed significantly between these host genes and host genes of miRNAs that do not contain potential miRNA binding sites. We then transferred these in-silico results to a biological example and investigated the relationship between ZFR and its intronic miRNA miR-579 in a U87 cell line model. We found that ZFR is targeted by its intronic miRNA miR-579 and that alternative polyadenylation allows differential targeting. We additionally used bioinformatics analyses and RNA-Seq to evaluate a potential cross-talk between intronic miRNAs and alternative polyadenylation. CPSF2, a gene previously associated with alternative polyadenylation signal recognition, might be linked to intronic miRNA negative feedback by altering polyadenylation signal utilization.
authors: Research Group Molecular Medicine, Department of Anaesthesiology, Clinic of the University of Munich, Munich, Germany.
authors: Ludwig Christian
authors: LC
authors: Hinske
authors: Molecular Oncology Center, Sírio Libanês Hospital, São Paulo, Brazil.
authors: Pedro A F
authors: PA
authors: Galante
authors: Molecular Oncology Center, Sírio Libanês Hospital, São Paulo, Brazil.
authors: Elisabeth
authors: E
authors: Limbeck
authors: Research Group Molecular Medicine, Department of Anaesthesiology, Clinic of the University of Munich, Munich, Germany.
authors: Patrick
authors: P
authors: Möhnle
authors: Molecular Oncology Center, Sírio Libanês Hospital, São Paulo, Brazil.
authors: Raphael B
authors: RB
authors: Parmigiani
authors: Division of Biomedical Informatics, University of California San Diego, La Jolla, California, United States of America.
authors: Lucila
authors: L
authors: Ohno-Machado
authors: Molecular Oncology Center, Sírio Libanês Hospital, São Paulo, Brazil.
authors: Anamaria A
authors: AA
authors: Camargo
authors: Research Group Molecular Medicine, Department of Anaesthesiology, Clinic of the University of Munich, Munich, Germany.
authors: Simone
authors: S
authors: Kreth
mesh_terms: D045744:Cell Line, Tumor; D039223:Cleavage And Polyadenylation Specificity Factor / Q000235:genetics; D019295:Computational Biology; D025461:Feedback, Physiological; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics*; D026723:Polyadenylation; D016601:RNA-Binding Proteins / Q000235:genetics*
chemical_list: D039223:Cleavage And Polyadenylation Specificity Factor; C000604992:MIRN579 microRNA, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C485556:ZFR protein, human