title: Transcriptome-wide characterization of the endogenous miR-34A-p53 tumor suppressor network.
abstract: microRNA-34A is a critical component of the p53 network and expression of miR- 34A is down-regulated by promoter hypermethylation or focal deletions in numerous human cancers. Although miR-34A deregulation may be an important driver in cancer, the endogenous role of this microRNA in cellular homeostasis is not well characterized. To address this knowledge gap, we aimed to determine the transcriptional landscape of the miR-34A-p53 axis in non-transformed cells. Using primary skin-derived fibroblast cell lines from patients who developed childhood cancers, and who harbor either germline TP53 mutations or are TP53 wild type, we sought to characterize the transcriptional response to miR-34A modulation. Through transcriptome-wide RNA-Sequencing, we show for the first time that in human non- transformed cells harboring TP53 mutations, miR-34A functions in a noncanonical manner to influence noncoding RNA networks, including RNA components of the minor (U12) spliceosome, as well as TP53-dependent and independent epigenetic pathways. miR- 34A-regulated transcripts include known cell cycle mediators and abrogation of miR-34A leads to a TP53-dependent increase in the fraction of cells in G2/M. Collectively, these results provide a framework for understanding the endogenous role of the miR-34A signaling axis and identify novel transcripts and pathways regulated by the essential miR-34A-p53 tumor suppressor network.
authors.affiliation: Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Canada.|Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Canada.|Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Nardin
authors.initials: N
authors.lastname: Samuel
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Canada.|Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, Canada.
authors.forename: Gavin
authors.initials: G
authors.lastname: Wilson
authors.affiliation: Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Badr
authors.initials: B
authors.lastname: Id Said
authors.affiliation: Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Pan
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Deblois
authors.affiliation: Department of Physical Sciences, Sunnybrook Research Institute, Toronto, Canada.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Fischer
authors.affiliation: The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Roumiana
authors.initials: R
authors.lastname: Alexandrova
authors.affiliation: The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Casallo
authors.affiliation: The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Tara
authors.initials: T
authors.lastname: Paton
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lupien
authors.affiliation: Department of Physical Sciences, Sunnybrook Research Institute, Toronto, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Gariepy
authors.affiliation: The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Daniele
authors.initials: D
authors.lastname: Merico
authors.affiliation: Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Canada.|Ontario Institute for Cancer Research, Toronto, Canada.|Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, Canada.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hudson
authors.affiliation: Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Canada.|Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Canada.|Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Malkin
mesh_terms: D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D006706:Homeostasis; D006801:Humans; D007223:Infant; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics; D011401:Promoter Regions, Genetic; D017423:Sequence Analysis, RNA; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: TP53; cell cycle; miR-34A; non-coding RNA; p53