Abstract
Direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs) holds great promise for heart regeneration. Although great progress has been made in understanding the transcriptional and epigenetic mechanisms of iCM reprogramming, its translational regulation remains largely unexplored. Through integrative ribosome and transcriptomic profiling, we characterized the translational landscape of iCM reprogramming, and found extensive translatome repatterning during fibroblast conversion into iCM. Loss of function screening for translational regulators uncovered Ybx1 as a critical barrier to iCM induction. Knockdown of Ybx1 dramatically improved the efficiency and quality of iCM reprogramming. Mechanistically, depletion of Ybx1 de-repressed the translation of its direct targets Srf and Baf60c , both of which mediated, at least partially, the effect of Ybx1 depletion on iCM generation. Interestingly, upon removing Ybx1, Tbx5 alone could reprogram fibroblasts into iCMs that exhibit classic iCM molecular features and reprogramming trajectories revealed by our single cell dual-omics. In summary, we elucidated the translatome dynamics of iCM reprogramming and identified Ybx1 as a critical translational barrier to iCM generation, removing of which allowed single factor mediated iCM reprogramming.
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