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

Abstract

Mutations in the <i>LMNA</i> 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-accessible 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 transcription factor 1 (TEAD1) by mutant Lamin A/C at the nuclear membrane underlies the pathogenesis of Q353R<i>-LMNA-</i>related DCM. Inhibition of the Hippo pathway rescued the dysregulation of cardiac developmental genes by TEAD1 in <i>LMNA</i> mutant cardiomyocytes. Single-cell RNA-seq of cardiac tissues from patients with DCM with the <i>LMNA</i> mutation confirmed the dysregulated expression of TEAD1 target genes. Our results propose an intervention for transcriptional dysregulation as a potential treatment of <i>LMNA</i>-related DCM.