MBNL1-mediated regulation of differentiation RNAs promotes myofibroblast transformation and the fibrotic response

Jennifer Davis, Nathan Salomonis, Natasha Ghearing, Suh-Chin J. Lin, Jennifer Q. Kwong, Apoorva Mohan, Maurice S. Swanson and Jeffery D. Molkentin ()
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Jennifer Davis: Cincinnati Children's Hospital Medical Center
Nathan Salomonis: Cincinnati Children's Hospital Medical Center
Natasha Ghearing: Cincinnati Children's Hospital Medical Center
Suh-Chin J. Lin: Cincinnati Children's Hospital Medical Center
Jennifer Q. Kwong: Cincinnati Children's Hospital Medical Center
Apoorva Mohan: Center for NeuroGenetics, University of Florida, College of Medicine
Maurice S. Swanson: Center for NeuroGenetics, University of Florida, College of Medicine
Jeffery D. Molkentin: Cincinnati Children's Hospital Medical Center

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms10084

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