Network model integrated with multi-omic data predicts MBNL1 signals that drive myofibroblast activation

• Published in: iScience Vol. 26; no. 4; p. 106502
• Main Authors: Nelson, Anders R., Bugg, Darrian, Davis, Jennifer, Saucerman, Jeffrey J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.04.2023; Elsevier
• Subjects: Cell biology; Network modeling; Systems biology; Cell biology; Systems biology; Network modeling
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.106502

RNA-binding protein muscleblind-like1 (MBNL1) was recently identified as a central regulator of cardiac wound healing and myofibroblast activation. To identify putative MBNL1 targets, we integrated multiple genome-wide screens with a fibroblast network model. We expanded the model to include putative MBNL1-target interactions and recapitulated published experimental results to validate new signaling modules. We prioritized 14 MBNL1 targets and developed novel fibroblast signaling modules for p38 MAPK, Hippo, Runx1, and Sox9 pathways. We experimentally validated MBNL1 regulation of p38 expression in mouse cardiac fibroblasts. Using the expanded fibroblast model, we predicted a hierarchy of MBNL1 regulated pathways with strong influence on αSMA expression. This study lays a foundation to explore the network mechanisms of MBNL1 signaling central to fibrosis. [Display omitted] •Integrated model predicts MBNL1 signaling targets affecting myofibroblast activation•Predicted that MBNL1 targets drive myofibroblast activation via redundant signaling•Predicted MBNL1 regulatory mechanisms for Hippo, Runx, Sox9, and p38 pathways•MBNL1 knockdown reduces p38 protein expression in mouse cardiac fibroblasts Cell biology; Network modeling; Systems biology