Faculty, Staff and Student Publications
Publication Date
2-27-2024
Journal
Cardiovascular Research
DOI
10.1093/cvr/cvad166
PMID
37890031
PMCID
PMC10898938
PubMedCentral® Posted Date
10-27-2023
PubMedCentral® Full Text Version
Post-print
Abstract
Aims: RNA binding proteins play essential roles in mediating RNA splicing and are key post-transcriptional regulators in the heart. Our recent study demonstrated that RBPMS (RNA binding protein with multiple splicing) is crucial for cardiac development through modulating mRNA splicing, but little is known about its functions in the adult heart. In this study, we aim to characterize the post-natal cardiac function of Rbpms and its mechanism of action.
Methods and results: We generated a cardiac-specific knockout mouse line and found that cardiac-specific loss of Rbpms caused severe cardiomyocyte contractile defects, leading to dilated cardiomyopathy and early lethality in adult mice. We showed by proximity-dependent biotin identification assay and mass spectrometry that RBPMS associates with spliceosome factors and other RNA binding proteins, such as RBM20, that are important in cardiac function. We performed paired-end RNA sequencing and RT-PCR and found that RBPMS regulates mRNA alternative splicing of genes associated with sarcomere structure and function, such as Ttn, Pdlim5, and Nexn, generating new protein isoforms. Using a minigene splicing reporter assay, we determined that RBPMS regulates target gene splicing through recognizing tandem intronic CAC motifs. We also showed that RBPMS knockdown in human induced pluripotent stem cell-derived cardiomyocytes impaired cardiomyocyte contraction.
Conclusion: This study identifies RBPMS as an important regulator of cardiomyocyte contraction and cardiac function by modulating sarcomeric gene alternative splicing.
Keywords
Animals, Humans, Mice, Alternative Splicing, Connectin, Induced Pluripotent Stem Cells, Mice, Knockout, Myocytes, Cardiac, RNA, RNA Splicing, RNA, Messenger, RNA-Binding Proteins, RNA binding protein, Cardiomyocyte contraction, Dilated cardiomyopathy, Titin, Pdlim5
Published Open-Access
yes
Recommended Citation
Gan, Peiheng; Wang, Zhaoning; Bezprozvannaya, Svetlana; et al., "Rbpms Regulates Cardiomyocyte Contraction and Cardiac Function Through RNA Alternative Splicing" (2024). Faculty, Staff and Student Publications. 761.
https://digitalcommons.library.tmc.edu/uthshis_docs/761
Graphical Abstract