Cardiac Troponin I(cTnI)is a subunit of the thin filament involved in regulation of heart contraction.Mutated cTnI accounts for most genetic mutations associated with restric-tive cardiomyopathy(RCM).We previously fou...Cardiac Troponin I(cTnI)is a subunit of the thin filament involved in regulation of heart contraction.Mutated cTnI accounts for most genetic mutations associated with restric-tive cardiomyopathy(RCM).We previously found phosphodiesterase 4D(PDE4D)decreased in RCM mice with cTnIR193H mutation and the mutant cTnI might be involved in PDE4D reduction.This study aims to elucidate a novel role of cTnIR193H mutant as a gene regulator.Overexpres-sion of cTnIR193H mutant in cardiomyocytes showed decrease in PDED4D protein expression,while the enrichment of histone deacetylase 1(HDAC1)was increased along with decreases in acetylated lysine 4(acH3K4)and 9(acH3K9)levels in the PDE4D promoter.HDAC1 overex-pression could also downregulate PDE4D via reducing acH3K4 and acH3K9 levels.Co-IP assays showed that cTnIR193H mutant owed increased binding ability to HDAC1 compared with wild type cTnI.EGCG as a HDAC1 inhibitor could diminish the strength of cTnIR193H-HDAC1 inter-actions and alleviate the reduction in PDE4D expression.Together,our data indicated that cTnIR193H mutant could repress PDE4D expression in cardiomyocytes through HDAC1 associ-ated histone deacetylation modification.Unlike the typical function of cTnI in cytoplasm,our study suggested a novel role of cTnI mutants in nuclei in regulating gene expression.展开更多
基金This study was supported by research grants from National Natural Science Foundation of China[grant number 81700214].
文摘Cardiac Troponin I(cTnI)is a subunit of the thin filament involved in regulation of heart contraction.Mutated cTnI accounts for most genetic mutations associated with restric-tive cardiomyopathy(RCM).We previously found phosphodiesterase 4D(PDE4D)decreased in RCM mice with cTnIR193H mutation and the mutant cTnI might be involved in PDE4D reduction.This study aims to elucidate a novel role of cTnIR193H mutant as a gene regulator.Overexpres-sion of cTnIR193H mutant in cardiomyocytes showed decrease in PDED4D protein expression,while the enrichment of histone deacetylase 1(HDAC1)was increased along with decreases in acetylated lysine 4(acH3K4)and 9(acH3K9)levels in the PDE4D promoter.HDAC1 overex-pression could also downregulate PDE4D via reducing acH3K4 and acH3K9 levels.Co-IP assays showed that cTnIR193H mutant owed increased binding ability to HDAC1 compared with wild type cTnI.EGCG as a HDAC1 inhibitor could diminish the strength of cTnIR193H-HDAC1 inter-actions and alleviate the reduction in PDE4D expression.Together,our data indicated that cTnIR193H mutant could repress PDE4D expression in cardiomyocytes through HDAC1 associ-ated histone deacetylation modification.Unlike the typical function of cTnI in cytoplasm,our study suggested a novel role of cTnI mutants in nuclei in regulating gene expression.
