Zinc Finger Protein Znf296 Is a Cardiac-Specific Splicing Regulator Required for Cardiomyocyte Formation

Area of Science:

• Cardiovascular Biology
• Molecular Genetics
• Developmental Biology

Background:

• Heart failure is a complex cardiovascular disease with unclear single-gene causes.
• Cardiac gene regulation at transcriptional and post-transcriptional levels is vital for heart function.
• Dysfunctional cardiac regulatory genes contribute to various heart diseases.

Purpose of the Study:

• To investigate the role of the zinc finger protein Znf296 in heart development and cardiac function.
• To elucidate the molecular mechanisms by which Znf296 influences cardiomyocyte structure and contractility.
• To determine if Znf296's function in heart development is conserved across species.

Main Methods:

• Utilized zebrafish (Danio rerio) as a model organism to study heart development.
• Generated znf296-deficient zebrafish embryos to observe cardiac phenotypes.
• Analyzed cardiomyocyte structure, cytoskeleton, and sarcomere organization.
• Investigated the impact of Znf296 deficiency on alternative splicing of key cardiac genes.
• Examined the interaction between Znf296 and myelin transcription factor 1-like (Myt1la).
• Assessed ZNF296's role in human cardiomyocytes.

Main Results:

• Znf296 deficiency in zebrafish led to significant heart defects, including reduced ventricular and atrial capacities.
• Cardiomyocytes in deficient embryos showed reduced numbers, disorganized cytoskeleton, and absent sarcomeres.
• Loss of Znf296 altered the alternative splicing of essential genes involved in heart development and disease (e.g., mef2ca, sparc, tpm2).
• Znf296 physically and functionally interacted with Myt1la to regulate cardiac splicing and development.
• ZNF296 was found to regulate alternative splicing in human cardiomyocytes, maintaining structural integrity.

Conclusions:

• Znf296 is essential for proper heart development and cardiac contractile function.
• The protein regulates cardiomyocyte differentiation and structural integrity through control of alternative splicing.
• Znf296's role in maintaining cardiovascular health is conserved between zebrafish and humans.
• Znf296 represents a potential target for understanding and treating heart diseases related to splicing defects.