YAP/TEAD1 Complex Is a Default Repressor of Cardiac Toll-Like Receptor Genes

Area of Science:

• Immunology
• Cardiovascular Biology
• Molecular Genetics

Background:

• Toll-like receptors (TLRs) are crucial pattern recognition receptors (PRRs) involved in innate immunity and heart disease.
• Molecular mechanisms regulating cardiac TLR gene expression remain incompletely understood.
• Hippo-YAP signaling is vital for cardiac development and homeostasis, with YAP/TEAD1 as its effector.

Purpose of the Study:

• To investigate the expression patterns of cardiac TLR genes (Tlr1-9) during mouse heart development and in response to pathological stress.
• To elucidate the role of the YAP/TEAD1 complex in regulating cardiac TLR gene expression.
• To determine the impact of YAP/TEAD1 on cardiac innate immune responses and stress susceptibility.

Main Methods:

• Quantitative analysis of TLR gene expression in mouse hearts at different developmental stages and under pathological conditions.
• Chromatin immunoprecipitation sequencing (ChIP-seq) to identify TEAD1 binding sites near TLR genes.
• Luciferase reporter assays to assess YAP/TEAD1 regulation of TLR4.
• In vivo studies using cardiomyocyte-specific YAP depletion in mice.

Main Results:

• Cardiac TLR3, TLR7, TLR8, and TLR9 expression increased with age, while TLR5 decreased.
• Pathological stress elevated the expression of TLR2, TLR4, TLR5, TLR7, TLR8, and TLR9.
• TEAD1 directly binds to genomic regions near most examined TLR genes.
• YAP/TEAD1 represses TLR4 expression, and cardiomyocyte-specific YAP depletion upregulates most cardiac TLR genes, promotes inflammation, and increases susceptibility to lipopolysaccharide stress.

Conclusions:

• Cardiac TLR gene expression is dynamically regulated by age and pathological stress.
• The YAP/TEAD1 complex functions as a key repressor of cardiac TLR gene expression.
• YAP/TEAD1-mediated regulation of TLRs is critical for maintaining cardiac immune homeostasis and preventing stress-induced damage.