Unknown,Transcriptomics,Genomics,Proteomics

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Effect of Smyd1 conditional knockout on gene expression in skeletal muscle

ABSTRACT: Transcriptome analysis by RNA-seq of tibialis anterior muscle from control and Smyd1 myocyte-specific conditional knockout mice at 6 weeks of age. Smyd1 is a methyltransferase specifically expressed in striated muscle and CD8+ T cells. Smyd1 deficiency resulted in centronuclear myopathy primarily affecting fast-twitch muscle fibers. These results provide insight into how loss of Smyd1 altered transcriptional programs resulting in centronuclear myopathy. 6 animals per group (control and Smyd1 conditional knockout)

ORGANISM(S): Mus musculus

SUBMITTER: M. David Stewart

PROVIDER: E-GEOD-71679 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Mouse myofibers lacking the SMYD1 methyltransferase are susceptible to atrophy, internalization of nuclei and myofibrillar disarray.

Stewart M David MD Lopez Suhujey S Nagandla Harika H Soibam Benjamin B Benham Ashley A Nguyen Jasmine J Valenzuela Nicolas N Wu Harry J HJ Burns Alan R AR Rasmussen Tara L TL Tucker Haley O HO Schwartz Robert J RJ

Disease models & mechanisms 20160301 3

The Smyd1 gene encodes a lysine methyltransferase specifically expressed in striated muscle. Because Smyd1-null mouse embryos die from heart malformation prior to formation of skeletal muscle, we developed a Smyd1 conditional-knockout allele to determine the consequence of SMYD1 loss in mammalian skeletal muscle. Ablation of SMYD1 specifically in skeletal myocytes after myofiber differentiation using Myf6(cre) produced a non-degenerative myopathy. Mutant mice exhibited weakness, myofiber hypotro ...[more]

PMID: 26935107

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Project description:Background: The histone-lysine N-methyltransferase SMYD1, which is specific to striated muscle, plays a crucial role in regulating early heart development. Its deficiency has been linked to the occurrence of congenital heart disease. Nevertheless, the precise mechanism by which SMYD1 deficiency contributes to congenital heart disease remains unclear. Methods: We established a SMYD1 knockout pluripotent stem cell line and a doxycyclineinducible SMYD1 expression pluripotent stem cell line to investigate the functions of SMYD1 utilizing an in vitro-directed myocardial differentiation model. Results: Cardiomyocytes lacking SMYD1 displayed drastically diminished differentiation efficiency, concomitant with heightened proliferation of cardiac progenitor cells during the early cardiac differentiation stage. These cellular phenotypes were confirmed through experiments inducing the re-expression of SMYD1. Transcriptome sequencing and small molecule inhibitor intervention suggested that the GSK3β/β-catenin/ERK signaling pathway was involved in the proliferation of cardiac progenitor cells. Chromatin immunoprecipitation demonstrated that SMYD1 acted as a transcriptional activator of GSK3β through histone H3 Lysine 4 trimethylation. Additionally, dualluciferase analyses indicated that SMYD1 could interact with the promoter region of GSK3β, thereby augmenting its transcriptional activity. Moreover, administering insulin and Insulin-like growth factor 1 can enhance the efficacy of myocardial differentiation in SMYD1 knockout cells. Conclusions: Our research indicated that the participation of SMYD1 in the GSK3β/β-catenin/ERK signaling cascade modulated the proliferation of cardiac progenitor cells during myocardial differentiation. This process was partly reliant on the transcription of GSK3β. Our research provided a novel insight into the genetic modification effect of SMYD1 during early myocardial differentiation. The findings were essential to the molecular mechanism and potential interventions for congenital heart disease.

Dataset Information

Effect of Smyd1 conditional knockout on gene expression in skeletal muscle

Publications

Mouse myofibers lacking the SMYD1 methyltransferase are susceptible to atrophy, internalization of nuclei and myofibrillar disarray.

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