Myocardial YBX1 is dispensable for cardiac development and function

Area of Science:

• Molecular Biology
• Cardiovascular Biology
• Genetics

Background:

• Yeast-binding protein X1 (YBX1) is a DNA/RNA-binding protein regulating gene expression and cellular functions.
• YBX1 dysregulation is implicated in heart disease, but its precise role in the heart is unclear due to conflicting findings from previous studies.
• Existing loss-of-function studies using RNA interference (RNAi) are limited by off-target effects and lack of cell specificity.

Purpose of the Study:

• To investigate the specific role of YBX1 in cardiomyocytes and its impact on cardiac function and development.
• To create and analyze cardiac-specific YBX1 knockout mouse models to overcome limitations of previous studies.
• To determine the safety of targeting YBX1 therapeutically in the context of heart disease.

Main Methods:

• Construction of global and cardiomyocyte-specific Ybx1 knockout (KO) mouse models.
• Phenotypic analysis of global Ybx1 KO mice, including assessment of embryonic lethality and cardiac development.
• Detailed evaluation of cardiomyocyte-specific Ybx1 KO (Ybx1^cmKO) mice for cardiac morphology, function, and gene expression changes using RNA-sequencing.

Main Results:

• Global Ybx1 KO mice exhibited embryonic lethality with severe cardiac defects, including noncompaction and impaired septal development.
• Ybx1^cmKO mice showed no apparent morphological abnormalities or cardiac dysfunction, indicating YBX1 is dispensable in cardiomyocytes for heart development and function.
• RNA-sequencing in Ybx1^cmKO hearts revealed upregulation of some fibrosis-related genes, but without resulting in cardiac fibrosis.

Conclusions:

• YBX1 is essential for embryonic development, with global loss leading to lethal cardiac defects.
• Specific deletion of YBX1 in cardiomyocytes does not induce cardiac hypertrophy, fibrosis, or dysfunction.
• Targeting YBX1 specifically within cardiomyocytes may be a safe therapeutic strategy for heart disease, but YBX1's role in other cardiac cell types requires careful consideration.