hnRNP U protein is required for normal pre-mRNA splicing and postnatal heart development and function

Area of Science:

• Molecular Biology
• Cardiovascular Biology
• Genetics

Background:

• Dilated cardiomyopathy is a severe heart condition.
• Cardiac pre-mRNA splicing is crucial for heart function.
• The role of heterogeneous nuclear ribonucleoprotein U (hnRNP U) in cardiac splicing is not fully understood.

Purpose of the Study:

• To investigate the role of hnRNP U in heart development and function.
• To identify the impact of hnRNP U deficiency on cardiac pre-mRNA splicing.
• To elucidate the molecular mechanisms underlying hnRNP U-mediated cardiac regulation.

Main Methods:

• Generation of mice lacking hnRNP U specifically in the heart.
• RNA sequencing (RNA-seq) analysis of mutant and control hearts.
• Analysis of cardiac morphology, contractility, and excitation-contraction coupling.

Main Results:

• Mice lacking cardiac hnRNP U developed lethal dilated cardiomyopathy with disorganized cardiomyocytes.
• Extensive defects in alternative splicing of key cardiac genes, including Titin, Camk2d, and Junctin, were observed.
• Aberrant splicing of Junctin affected protein glycosylation and partner interactions, impacting excitation-contraction coupling.

Conclusions:

• hnRNP U is essential for normal heart development and function.
• hnRNP U plays a critical role in regulating alternative pre-mRNA splicing in the heart.
• Defects in hnRNP U-mediated splicing contribute to dilated cardiomyopathy pathogenesis.