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

Mutations in the LMNA gene encoding Lamin A and C (Lamin A/C), major components of the nuclear lamina, cause laminopathies including dilated cardiomyopathy (DCM), but the underlying molecular mechanisms have not been fully elucidated. Here, by leveraging single-cell RNA sequencing (RNA-seq), assay for transposase-ac-cessible chromatin using sequencing (ATAC-seq), protein array, and electron microscopy analysis, we show that insufficient structural maturation of cardiomyocytes owing to trapping of transcription factor TEA domain tran-scription factor 1 (TEAD1) by mutant Lamin A/C at the nuclear membrane underlies the pathogenesis of Q353R- LMNA-related DCM. Inhibition of the Hippo pathway rescued the dysregulation of cardiac developmental genes by TEAD1 in LMNA mutant cardiomyocytes. Single-cell RNA-seq of cardiac tissues from patients with DCM with the LMNA mutation confirmed the dysregulated expression of TEAD1 target genes. Our results propose an in-tervention for transcriptional dysregulation as a potential treatment of LMNA-related DCM.

Automated summary

This study investigates the molecular mechanisms underlying dilated cardiomyopathy (DCM) caused by mutations in the LMNA gene. The researchers found that mutant Lamin A/C traps transcription factor TEAD1 at the nuclear membrane, leading to insufficient structural maturation of cardiomyocytes and the development of DCM. Inhibition of the Hippo pathway can rescue the dysregulation of cardiac developmental genes by TEAD1 in LMNA mutant cardiomyocytes. Single-cell RNA sequencing confirms the dysregulated expression of TEAD1 target genes in DCM patients with the LMNA mutation.