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

Author

Listed:
  • 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
    Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center)

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.

Suggested Citation

  • Jennifer Davis & Nathan Salomonis & Natasha Ghearing & Suh-Chin J. Lin & Jennifer Q. Kwong & Apoorva Mohan & Maurice S. Swanson & Jeffery D. Molkentin, 2015. "MBNL1-mediated regulation of differentiation RNAs promotes myofibroblast transformation and the fibrotic response," Nature Communications, Nature, vol. 6(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms10084
    DOI: 10.1038/ncomms10084
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    Cited by:

    1. Shea N. Ricketts & Gregory M. Farber & Sunil K. Verma & Yanhan Dong & Yifang Xie & Paige R. Takasugi & Shufen Chen & Luping Du & Haofei Wang & Wei Hui & Celine Keles & Sergey Tsoy & Grace Fuller & Mic, 2026. "Cardiac fibroblast deletion of PTBP1 modulates the profibrotic response by alternative splicing," Nature Communications, Nature, vol. 17(1), pages 1-24, December.

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