TEAD1 trapping by the Q353R-Lamin A/C causes dilated cardiomyopathy

Area of Science:

• Cardiovascular Biology
• Molecular Genetics
• Cellular Biology

Background:

• Mutations in the LMNA gene, encoding Lamin A/C, are linked to laminopathies, including dilated cardiomyopathy (DCM).
• The precise molecular mechanisms driving LMNA-related DCM remain incompletely understood.
• Lamin A/C are crucial structural components of the nuclear lamina in cardiomyocytes.

Purpose of the Study:

• To elucidate the molecular pathogenesis of Q353R-LMNA related dilated cardiomyopathy.
• To investigate the role of transcription factor TEAD1 in LMNA-mutant cardiomyocyte development.
• To explore potential therapeutic interventions targeting transcriptional dysregulation.

Main Methods:

• Single-cell RNA sequencing (RNA-seq) for gene expression profiling.
• Assay for transposase-accessible chromatin using sequencing (ATAC-seq) to assess chromatin accessibility.
• Protein array and electron microscopy for structural and molecular analysis.

Main Results:

• Mutant Lamin A/C sequesters transcription factor TEAD1 at the nuclear membrane, impairing cardiomyocyte structural maturation.
• TEAD1 trapping leads to dysregulation of cardiac developmental genes in LMNA mutant cardiomyocytes.
• Inhibition of the Hippo pathway ameliorated TEAD1-mediated gene dysregulation.
• Analysis of patient-derived cardiac tissues confirmed dysregulated expression of TEAD1 target genes.

Conclusions:

• TEAD1 sequestration by mutant Lamin A/C is a key mechanism in Q353R-LMNA related DCM pathogenesis.
• Targeting transcriptional dysregulation via Hippo pathway modulation presents a potential therapeutic avenue for LMNA-related DCM.
• Further research into TEAD1-Lamin A/C interactions could reveal novel therapeutic targets for laminopathies.