Cardiac troponin I R193H mutant interacts with HDAC1 to repress phosphodiesterase 4D expression in cardiomyocytes

作者全名："Zhao, Weian; Lu, Qian; Luo, Jing; Pan, Bo; Liu, Ling-Juan; Tian, Jie"

作者地址："[Zhao, Weian] Sun Yat Sen Univ, Dept Anesthesiol, Affiliated Hosp 1, Guangzhou 510080, Guangdong, Peoples R China; [Lu, Qian; Luo, Jing; Pan, Bo; Liu, Ling-Juan; Tian, Jie] Chongqing Med Univ, Dept Cardiol, Minist Educ,Key Lab Child Dev & Disorders,Childre, Chongqing Key Lab Pediat,China Int Sci & Technol, Chongqing 401122, Peoples R China"

通信作者："Tian, J (corresponding author), Chongqing Med Univ, Childrens Hosp, Dept Cardiol, Heart Ctr, Chongqing 400014, Peoples R China."

来源：GENES & DISEASES

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000661449300016

JCR分区：Q1

影响因子：6.8

年份：2021

卷号：8

期号：4

开始页：569

结束页：579

文献类型：Article

关键词：cTnIR93H; EGCG; HDAC1; Histone modifications; PDE4D reduction

摘要："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 restrictive 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. Overexpression 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 overexpression 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 interactions and alleviate the reduction in PDE4D expression. Together, our data indicated that cTnIR193H mutant could repress PDE4D expression in cardiomyocytes through HDAC1 associated 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. Copyright (C) 2020, Chongqing Medical University. Production and hosting by Elsevier B.V."

基金机构：National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81700214]

基金资助正文：This study was supported by research grants from National Natural Science Foundation of China [grant number 81700214].