UCLA

Cardiac hypertrophy is an adaptive process during hemodynamic stress induced by various pathophysiological conditions. During this process, individual myocyte grows bigger in size under complex and multi-layered regulations, which required a large amount of de novo protein synthesis. It has already been well-established back in the 1960s and 70s that protein synthesis is induced early on during induced hypertrophic stress, which is a dominating factor leading to hypertrophic myocytes and hearts. Over the years, scientists have extensively investigated different regulatory steps in cardiac hypertrophy, such as signaling pathways, transcription regulation, and metabolism. However, translation remained poorly studied. Moreover, recent discoveries on transcriptome/translatome mismatch brought these questions to our attention, as it is challenging the prevalent interpretation of the central dogma. Therefore, there’s a dire need to achieve a deeper understanding of translation regulation in cardiac hypertrophy to fill the knowledge gap and coordinate the conflict and discrepancies between the knowns and the novel discoveries. In this thesis, we discussed protein translation regulation in cardiac hypertrophy in many different aspects, including toolkits to study translation, translation efficiency, translation capacity, and the emerging field of spatial-temporal regulation of translation machinery. Aiming to obtain a comprehensive understanding of translation regulation in cardiac hypertrophy, we combined novel mouse and cell culture models with cutting-edge technologies including deep RNA sequencing and proteomics to investigate the translatome landscape and underlying molecular mechanisms. We identified striking remodeling of the translatome and nascent proteome during hypertrophic stress with an emphasis on ribosome biogenesis. We identified a long non-coding RNA (lncRNA) named Myocardial Infarction Associated Transcript (Miat) as a critical regulator of translation during cardiac hypertrophy. For molecular mechanisms, we demonstrated Miat interacts with a nucleolar protein nucleolin (NCL) to mediate ribosome biogenesis. We also discovered important regulatory roles of Miat in nucleolar (center of ribosome biogenesis) dynamics and transportation of translation machinery. Taken together, this thesis gave a holistic and comprehensive depiction of translation regulation in pathological cardia hypertrophy with a well-characterized lncRNA mediating multiple aspects of the translation process and translation machineries. Our study filled the knowledge gap in our understanding of cardiac hypertrophy and gave inspirations on protein synthesis regulation in heart, which could be generalized to many other non-cardiac contexts and lead to a paradigm shift. Our discoveries shed light on current clinical resolutions of cardiac hypertrophy and may potentially lead to the development of novel therapies.