Our research mainly uses human pluripotent stem cells as a model to explore the pathological mechanism of human heart development and heart disease. Cardiomyopathy is a common heart disease in which the heart cannot perform normal functions due to disease of the heart muscle. At present, the drugs for the treatment of cardiomyopathy are only supportive therapy, and there is no way to cure it. In the end, patients often need to wait for a heart transplant, otherwise they may die. Therefore, how to find an effective treatment method is an issue that needs to be solved at present.

The sarcomere is the basic unit of the myocardium, which is composed of hundreds of sarcomere proteins. Clinical studies have found that many sarcomere protein gene variations may lead to cardiomyopathy. Therefore, if we can understand the upstream molecular mechanism behind the formation of normal sarcomeres, it will help to find out more causes and potential treatments of cardiomyopathy. RBM24 (RNA-binding motif protein 24) is a known cardiac splicing factor, which can affect the structure of sarcomere through alternative splicing, but its function and molecular mechanism in myocardial development are still unclear. Therefore, the laboratory uses CRISPR/Cas9 technology to establish a human stem cell line lacking RBM24 to explore the role of RBM24 in myocardial development.

The research team found that RBM24 regulates many sarcomere-related proteins at different stages in the process of myocardial differentiation, and can be regarded as a master regulator of myocardial development. Among them, we found that the core myofibrilogenic proteins   (such as ACTN2, TTN and MYH10) that form the most important sarcomeres were misspliced. Thus, MYH6 does not normally replace the non-muscle myosin MYH10, leading to myofibril arrest at the early pre-myofibril stage and disruption of sarcomeres. Interestingly, we found that the actin-binding domain (ABD; encoded by exon 6) of the Z-line anchor protein ACTN2 is predominantly excluded (exon exclusion) during early cardiac differentiation, whereas it is eventually included (exon inclusion) in the adult heart. Finally, we demonstrated that RBM24 is involved in the important function of sarcomere formation in the early stage of cardiac differentiation, and its deletion will make exon 6 (Exon6) of ACTN2 be excluded (exon exclusion). At the same time, it was found that the sarcomere proteins regulated by RBM24 are closely related to cardiomyopathy when they mutate. Therefore, the team confirmed that RBM24 plays an important regulatory role in the process of myocardial development and acts as an upstream regulator of many cardiomyopathy genes. Therefore, This study is expected to provide a new treatment strategy for future cardiomyopathy. This research result was published in Circulation Research, an important international journal in the field of heart disease. It was completed by master class students Lu Huian (first author), Su Liangyu, and undergraduate students Li Kangzheng and Ye Yuchen.     

Growing human stem cells is expensive and there are no holidays, rain or shine. However, because human stem cells have unlimited potential in regenerative therapy, disease modeling and drug screening, the research team is still working hard, hoping that the team's research will one day contribute to the treatment of human diseases. I would like to thank the Ministry of Science and Technology and the school's financial support for the project, as well as the many seniors who silently helped the laboratory, and thank every student in the research team for their willingness to work hard for their ideals!
 

Full text of Circulation Research:https://www.ahajournals.org/doi/abs/10.1161/CIRCRESAHA.121.320080