Why the study?
RNA-binding protein muscleblind-like1 (MBNL1) was recently identified as a central regulator of cardiac wound healing and myofibroblast activation, but putative MBNL1 targets remained to be identified.
This study identifies key MBNL1-regulated signaling pathways, including p38 MAPK, that drive cardiac myofibroblast activation and fibrosis.
Should not change practice; leaves open whether redundant MBNL1 modules are selective antifibrotic targets in vivo.
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.
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Nelson et al. (2023) studied this question.
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