PT  - JOURNAL ARTICLE
AU  - Yuxuan Guo
AU  - Blake D. Jardin
AU  - Isha Sethi
AU  - Qing Ma
AU  - Behzad Moghadaszadeh
AU  - Emily C. Troiano
AU  - Michael A. Trembley
AU  - Eric M. Small
AU  - Guo-Cheng Yuan
AU  - Alan H. Beggs
AU  - William T. Pu
TI  - Sarcomeres regulate cardiomyocyte maturation through MRTF-SRF signaling
AID  - 10.1101/824185
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 824185
4099  - http://biorxiv.org/content/early/2019/11/13/824185.short
4100  - http://biorxiv.org/content/early/2019/11/13/824185.full
AB  - Cardiomyocyte maturation is essential for robust heart contraction throughout life. The signaling networks governing cardiomyocyte maturation remain poorly defined. Our prior studies established the transcription factor SRF as a key regulator of the assembly of sarcomeres, the contractile unit of cardiomyocytes. Whether sarcomeres regulate other aspects of maturation remains unclear. Here we generated mice with cardiomyocyte specific, mosaic mutation of α-actinin-2 (Actn2), a key organizer of sarcomeres, to study its cell-autonomous role in cardiomyocyte maturation. In addition to the expected structural defects, Actn2 mutation triggered dramatic transcriptional dysregulation, which strongly correlated with transcriptional changes observed in SRF-depleted cardiomyocytes. Actn2 mutation increased monomeric actin, which perturbed the nuclear localization of the SRF cofactor MRTFA. Overexpression of a dominant-negative MRTFA mutant was sufficient to recapitulate the transcriptional and morphological defects in Actn2 and Srf mutant cardiomyocytes. Together, we demonstrate that ACTN2-based sarcomere assembly and MRTF-SRF signaling establish a positive feedback loop that promotes cardiomyocyte maturation.