title: MBNL1-mediated regulation of differentiation RNAs promotes myofibroblast transformation and the fibrotic response.
abstract: The differentiation of fibroblasts into myofibroblasts mediates tissue wound healing and fibrotic remodelling, although the molecular programme underlying this process remains poorly understood. Here we perform a genome-wide screen for genes that control myofibroblast transformation, and identify the RNA-binding protein muscleblind-like1 (MBNL1). MBNL1 overexpression promotes transformation of fibroblasts into myofibroblasts, whereas loss of Mbnl1 abrogates transformation and impairs the fibrotic phase of wound healing in mouse models of myocardial infarction and dermal injury. Mechanistically, MBNL1 directly binds to and regulates a network of differentiation-specific and cytoskeletal/matrix-assembly transcripts to promote myofibroblast differentiation. One of these transcripts is the nodal transcriptional regulator serum response factor (SRF), whereas another is calcineurin Aβ. CRISPR-Cas9-mediated gene-editing of the MBNL1-binding site within the Srf 3'UTR impairs myofibroblast differentiation, whereas in vivo deletion of Srf in fibroblasts impairs wound healing and fibrosis. These data establish a new RNA-dependent paradigm for myofibroblast formation through MBNL1.
authors.affiliation: Cincinnati Children's Hospital Medical Center, Department of Pediatrics, Cincinnati, Ohio 45229, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Davis
authors.affiliation: Cincinnati Children's Hospital Medical Center, Department of Pediatrics, Cincinnati, Ohio 45229, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Salomonis
authors.affiliation: Cincinnati Children's Hospital Medical Center, Department of Pediatrics, Cincinnati, Ohio 45229, USA.
authors.forename: Natasha
authors.initials: N
authors.lastname: Ghearing
authors.affiliation: Cincinnati Children's Hospital Medical Center, Department of Pediatrics, Cincinnati, Ohio 45229, USA.
authors.forename: Suh-Chin J
authors.initials: SC
authors.lastname: Lin
authors.affiliation: Cincinnati Children's Hospital Medical Center, Department of Pediatrics, Cincinnati, Ohio 45229, USA.
authors.forename: Jennifer Q
authors.initials: JQ
authors.lastname: Kwong
authors.affiliation: Department of Molecular Genetics and Microbiology, Center for NeuroGenetics, University of Florida, College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: Apoorva
authors.initials: A
authors.lastname: Mohan
authors.affiliation: Department of Molecular Genetics and Microbiology, Center for NeuroGenetics, University of Florida, College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: Maurice S
authors.initials: MS
authors.lastname: Swanson
authors.affiliation: Cincinnati Children's Hospital Medical Center, Department of Pediatrics, Cincinnati, Ohio 45229, USA.|Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio Ohio 45229, USA.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000166:cytology* / Q000378:metabolism*; D012313:RNA / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing
chemical_list: D004268:DNA-Binding Proteins; C479922:Mbnl1 protein, mouse; D016601:RNA-Binding Proteins; D012313:RNA