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PRDM16 determines specification of ventricular cardiomyocytes by suppressing alternative cell fates
Jore Van Wauwe1, Alexia Mahy1, Sander Craps1
1Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.
Insights
PRDM16 is crucial for heart development, promoting ventricular cardiomyocyte identity. Its loss causes severe cardiac dysfunction and premature death in mice, highlighting its role in preventing conduction system abnormalities.
Area of Science:
- Cardiovascular Biology
- Developmental Biology
- Molecular Cardiology
Background:
- PRDM16, a transcription factor with histone methyltransferase activity, is vital in early cardiac development.
- Mutations in PRDM16 are linked to human cardiomyopathies, conduction defects, and heart failure.
- PRDM16 expression is specific to ventricular cardiomyocytes and decreases postnatally.
Purpose of the Study:
- To investigate the role of PRDM16 in cardiomyocyte cell fate decisions during cardiac development.
- To determine the impact of PRDM16 deletion on heart function and cardiomyocyte identity.
Main Methods:
- Generated cardiomyocyte-specific Prdm16 knockout mouse models.
- Utilized combined RNA and ATAC single-cell sequencing (scRNA-seq and scATAC-seq) for comprehensive analysis.
- Assessed cardiac function, electrophysiology, and conduction system development.
Main Results:
- Cardiomyocyte-specific deletion of Prdm16 led to severe contractile dysfunction, abnormal electrophysiology, and premature death.
- PRDM16 was found to promote ventricular working cardiomyocyte identity by antagonizing regulators of conduction and atrial fate.
- Loss of PRDM16 resulted in hyperplasia of the ventricular conduction system.
Conclusions:
- PRDM16 is essential for establishing and maintaining ventricular working cardiomyocyte identity during cardiac development.
- PRDM16 acts as a key regulator, preventing the inappropriate development of conduction system tissues.
- Understanding PRDM16's function provides insights into congenital heart defects and cardiomyopathies.
Abstract:
PRDM16 is a transcription factor with histone methyltransferase activity expressed at the earliest stages of cardiac development. Pathogenic mutations in humans lead to cardiomyopathy, conduction abnormalities, and heart failure. PRDM16 is specifically expressed in ventricular but not atrial cardiomyocytes, and its expression declines postnatally. Because in other tissues PRDM16 is best known for its role in binary cell fate decisions, we hypothesized a similar decision-making function in cardiomyocytes. Here, we demonstrated that cardiomyocyte-specific deletion of Prdm16 during cardiac development results in contractile dysfunction and abnormal electrophysiology of the postnatal heart, resulting in premature death. By combined RNA+ATAC single-cell sequencing, we found that PRDM16 favors ventricular working cardiomyocyte identity, by opposing the activity of master regulators of ventricular conduction and atrial fate. Myocardial loss of PRDM16 during development resulted in hyperplasia of the (distal) ventricular conduction system. Hence, PRDM16 plays an indispensable role during cardiac development by driving ventricular working cardiomyocyte identity.
