2. Academic Validation
  3. Intranuclear cardiac troponin I plays a functional role in regulating Atp2a2 expression in cardiomyocytes

Intranuclear cardiac troponin I plays a functional role in regulating Atp2a2 expression in cardiomyocytes

  • Genes Dis. 2021 May 15;9(6):1689-1700. doi: 10.1016/j.gendis.2021.04.007.
Qian Lu 1 2 3,  Bo Pan 1 2,  Haobo Bai 4,  Weian Zhao 1 2,  Lingjuan Liu 1 2,  Gu Li 1 2,  Ruimin Liu 1 2,  Tiewei Lv 1 2,  Xupei Huang 3,  Xi Li 5,  Jie Tian 1 2
Affiliations

Affiliations

  • 1 Department of Pediatric Cardiology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, PR China.
  • 2 Chongqing Key Laboratory of Pediatrics, Chongqing 400014, PR China.
  • 3 Department of Biomedical Science, Charlie E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA.
  • 4 Department of Orthopedic, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China.
  • 5 Biology Science Institutes of Chongqing Medical University, Chongqing 400016, PR China.
PMID: 36157491 DOI: 10.1016/j.gendis.2021.04.007
Abstract

In the past studies, it is shown that cardiac troponin I (cTnI, encoded by TNNI3), as a cytoplasmic protein, is an inhibitory subunit in troponin complex, and involves in cardiomyocyte diastolic regulation. Here, we assessed a novel role of cTnI as a nucleoprotein. Firstly, the nuclear translocation of cTnI was found in mouse, human fetuses and rat heart tissues. In addition, there were differences in percentage of intranuclear cTnI in different conditions. Based on weighted gene co-expression network analyses (WGCNA) and verification in cell experiments, a strong expression correlation was found between TNNI3 and Atp2a2, which encodes sarco-endoplasmic reticulum CA2+ ATPase isoform 2a (SERCA2a), and involves in ATP hydrolysis and CA2+ transient. TNNI3 gain and loss caused Atpa2a2 increase/decrease in a dose-dependent manner both in mRNA and protein levels, in vivo and in vitro. By using ChIP-sequence we demonstrated specific binding DNA sequences of cTnI were enriched in ATP2a2 promoter -239∼-889 region and the specific binding sequence motif of cTnI was analyzed by software as "CCAT", which has been reported to be required for YY1 binding to the promoter region of YY1-related genes. Moreover, it was further verified that pcDNA3.1 (-)-TNNI3 could express cTnI proteins and increase the promoter activity of Atp2a2 through luciferase report assay. In the end, we evaluated beat frequencies, total ATP contents, CA2+ transients in TNNI3-siRNA myocardial cells. These findings indicated, for the first time, cTnI may regulate Atp2a2 in cardiomyocytes as a co-regulatory factor and participate in the regulation of intracellular CA ions.

Keywords

Atp2a2; Ca ions; Intranuclear cardiac troponin I; Nuclear translocation; YY1.

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