Regulation of the Translatome in Cardiac Remodeling

Abstract

Gene expression is determined by both transcriptional as well as multiple layers of post‐transcriptional controls, including protein translation. One of the molecular hallmark observed in diseased hearts is augmented protein synthesis and marked reprogramming of translatome (defined as ribosomal loaded mRNAs). Furthermore, translatome reprogramming is often independent from the concurrent total transcriptome changes. However, the underlying dynamics and regulatory network remain largely unexplored. In this study, we observed a robust induction of protein synthesis associated with a rapid change of ribosome loaded mRNAs in response to hypertrophic stimulation in cultured myocytes and intact mouse hearts, associated with dynamic changes in nucleoli organization. This early onset of translatome reprogramming and subsequent protein synthesis induction requires the induction of a long non‐coding RNA (lncRNA) named Myocardial Infarction Associated Transcript (Miat). Molecular characterization reveals that Miat is specifically localized in nuclei and interacts with Nucleolin (NCL). Miat expression is essential for NCL mediated ribosome biogenesis and function. In Miat KO mouse hearts or cultured myocytes, pathological hypertrophy is significantly blunted in vitro and in vivo, along with blocked rRNA biogenesis and processing, and protein synthesis. These findings offer the first evidence that ribosome biogenesis and translatome reprogramming is an essential early molecular process of pathological hypertrophy in heart. Miat‐NCL mediated translatome reprogramming induced by pathological stimulation is a novel regulatory corner stone and post‐transcriptional check‐point for pathological hypertrophy and heart failure.