Science advances · 2023
TEAD1 trapping by the Q353R-Lamin A/C causes dilated cardiomyopathy.
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Yamada Shintaro, Ko Toshiyuki, Ito Masamichi, Sassa Tatsuro, Nomura Seitaro, Okuma Hiromichi, Sato Mayuko, Imasaki Tsuyoshi, Kikkawa Satoshi, Zhang Bo, Yamada Takanobu, Seki Yuka, Fujita Kanna, Katoh Manami, Kubota Masayuki, Hatsuse Satoshi, Katagiri Mikako, Hayashi Hiromu, Hamano Momoko, Takeda Norifumi, Morita Hiroyuki, Takada Shuji, Toyoda Masashi, Uchiyama Masanobu, Ikeuchi Masashi, Toyooka Kiminori, Umezawa Akihiro, Yamanishi Yoshihiro, Nitta Ryo, Aburatani Hiroyuki, Komuro Issei
Аннотация
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-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-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 intervention for transcriptional dysregulation as a potential treatment of LMNA-related DCM.