Dissecting the molecular and epigenetic role of Smyd1 in sarcomeric renewal and regeneration in cardiomyocytes

• Applicant: Professor Dr. Steffen Just
• Subject Area: Cardiology, Angiology ; Developmental Biology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 417702515

The methyltransferase SET- and MYND-domain-containing protein 1b (Smyd1b) is specifically expressed in the heart and fast-twitch skeletal muscle cells in zebrafish. Within these cell types, Smyd1b localizes to both the nucleus, where it supposedly regulates transcription through its SET and MYND domains and the sarcomeric M-line, where it physically associates with Myosin. Additionally, Smyd1 was shown to form a complex with the Myosin chaperones Hsp90a and Unc45b and thus contributes to myofibrillogenesis in cardiomyocytes. In addition to their physical interaction, hsp90a1, unc45b and smyd1b are part of a complex gene program that is activated through defective myosin folding and assembly (termed misfolded myosin response (MMR)) leading to their massive transcriptional induction. During the last funding period, Smyd1b-mediated Myosin methylation at position K35 was shown to play an essential role in Myosin homeostasis and its assembly into functional sarcomeres in developing cardiomyocytes. Whether Smyd1b function is also critical for Myosin homeostasis and sarcomere assembly during cardiac regeneration, particularly the de-differentiation and re-differentiation of proliferating cardiomyocytes, in the adult zebrafish heart is not studied so far. Furthermore, whether the role of SMYD1 in the methylation of sarcomeric MYOSIN is conserved in human cardiomyocytes is also completely unknown. Due to our recent findings on the important role of Smyd1 on the methylation of sarcomeric Myosin, its assembly and homeostasis during cardiac development, we will now focus this research project on the impact of Smyd1 on (1) Myosin methylation, cardiomyocyte de-dedifferentiation, sarcomeric breakdown, and functional cardiomyocyte re-differentiation during the regeneration of the adult zebrafish heart. Secondly, we will aim to (2) translate our recent zebrafish Smyd1 findings into the mammalian/human system by investigating the role SMYD1 on MYOSIN methylation, sarcomeric assembly and cardiomyocyte function in human iPSC-derived cardiomyocytes. The long-term goal of this project is to foster regenerative strategies as therapeutic options for acute or chronic myocardial injury. In this context, in vitro and in vivo approaches, particularly the use of a newly established CRISPR/Cas9-mediated floxed Smyd1 zebrafish line as well as AAV-mediated SMYD1 ablation in human iPSC-derived cardiomyocytes will be applied.

• DFG Programme: Research Grants