title: RNA helicases DDX5 and DDX17 dynamically orchestrate transcription, miRNA, and splicing programs in cell differentiation.
abstract: The RNA helicases DDX5 and DDX17 are members of a large family of highly conserved proteins that are involved in gene-expression regulation; however, their in vivo targets and activities in biological processes such as cell differentiation, which requires reprogramming of gene-expression programs at multiple levels, are not well characterized. Here, we uncovered a mechanism by which DDX5 and DDX17 cooperate with heterogeneous nuclear ribonucleoprotein (hnRNP) H/F splicing factors to define epithelial- and myoblast-specific splicing subprograms. We then observed that downregulation of DDX5 and DDX17 protein expression during myogenesis and epithelial-to-mesenchymal transdifferentiation contributes to the switching of splicing programs during these processes. Remarkably, this downregulation is mediated by the production of miRNAs induced upon differentiation in a DDX5/DDX17-dependent manner. Since DDX5 and DDX17 also function as coregulators of master transcriptional regulators of differentiation, we propose to name these proteins "master orchestrators" of differentiation that dynamically orchestrate several layers of gene expression.
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; Université Claude Bernard Lyon 1, 69008 Lyon, France; Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Dardenne
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; Université Claude Bernard Lyon 1, 69008 Lyon, France; Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Micaela
authors.initials: M
authors.lastname: Polay Espinoza
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; Université Claude Bernard Lyon 1, 69008 Lyon, France; Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Fattet
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; Université Claude Bernard Lyon 1, 69008 Lyon, France; Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Germann
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; Université Claude Bernard Lyon 1, 69008 Lyon, France; Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Lambert
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; Université Claude Bernard Lyon 1, 69008 Lyon, France; Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Helen
authors.initials: H
authors.lastname: Neil
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; Université Claude Bernard Lyon 1, 69008 Lyon, France; Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Zonta
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; Université Claude Bernard Lyon 1, 69008 Lyon, France; Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Hussein
authors.initials: H
authors.lastname: Mortada
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; Université Claude Bernard Lyon 1, 69008 Lyon, France; Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Lise
authors.initials: L
authors.lastname: Gratadou
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; Université Claude Bernard Lyon 1, 69008 Lyon, France; Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Deygas
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; Université Claude Bernard Lyon 1, 69008 Lyon, France; Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Fatima Zahra
authors.initials: FZ
authors.lastname: Chakrama
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; Université Claude Bernard Lyon 1, 69008 Lyon, France; Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Samaan
authors.initials: S
authors.lastname: Samaan
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; Université Claude Bernard Lyon 1, 69008 Lyon, France; Centre Léon Bérard, 69008 Lyon, France.
authors.forename: François-Olivier
authors.initials: FO
authors.lastname: Desmet
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; Université Claude Bernard Lyon 1, 69008 Lyon, France; Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Léon-Charles
authors.initials: LC
authors.lastname: Tranchevent
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; Université Claude Bernard Lyon 1, 69008 Lyon, France; Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Dutertre
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; Université Claude Bernard Lyon 1, 69008 Lyon, France; Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Ruth
authors.initials: R
authors.lastname: Rimokh
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; Université Claude Bernard Lyon 1, 69008 Lyon, France; Centre Léon Bérard, 69008 Lyon, France. Electronic address: cyril.bourgeois@inserm.fr.
authors.forename: Cyril F
authors.initials: CF
authors.lastname: Bourgeois
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; Université Claude Bernard Lyon 1, 69008 Lyon, France; Centre Léon Bérard, 69008 Lyon, France. Electronic address: didier.auboeuf@inserm.fr.
authors.forename: Didier
authors.initials: D
authors.lastname: Auboeuf
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005091:Exons; D005786:Gene Expression Regulation; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D032446:Myoblasts / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D014158:Transcription, Genetic
chemical_list: D034441:Heterogeneous-Nuclear Ribonucleoproteins; D035683:MicroRNAs; C102004:DDX17 protein, human; C577630:Ddx17 protein, mouse; C506749:Ddx5 protein, human; C506751:Ddx5 protein, mouse; D053487:DEAD-box RNA Helicases