Mechano-regulated RNA binding protein hnRNPC contributes to RNA homeostasis in heart failure

Cardiac pathologies are characterized by intense remodeling of the extracellular matrix (ECM) that eventually leads to heart failure. Cardiomyocytes respond to the ensuing biomechanical stress by re-expressing fetal contractile proteins via transcriptional and post-transcriptional processes, like alternative splicing (AS). Here, we demonstrate that the heterogeneous nuclear ribonucleoprotein C (hnRNPC) is upregulated and relocates to the sarcomeric Z-disk upon ECM pathological remodeling. At this site, the protein participates to the localized translation of mRNAs encoding sarcomeric proteins. Alterations in hnRNPC expression and localization can be mechanically determined and affect the AS of numerous mRNAs involved in mechanotransduction and cardiovascular diseases. We thus propose that cardiac ECM remodeling serves as a switch in RNA metabolism by directly impacting an associated regulatory protein of the spliceosome apparatus. These findings offer new insights on the mechanism of mRNAs homeostasis mechanoregulation in disease conditions. iCLIP-seq : Individual-nucleotide resolution UV crosslinking and immunoprecipitation (iCLIP) of hnRNPC1/C2 in normal human dermal fibroblasts (NHDFs)