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

Lü, Qian; Pan, Bo; Bai, Haobo; Zhao, Weian; Liu, Lingjuan; Li, Gu; Liu, Ruimin; Lv, Tiewei; Huang, Xupei; Li, Xi; Tian, Jie

doi:10.1016/j.gendis.2021.04.007

Cited by 9 publications

(28 citation statements)

References 35 publications

(53 reference statements)

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“…FOS was proved to bind with the ATG5 promoter and was critical for reducing ATG5 transcription in ageing-associated cardiac autophagy impairment. Some studies have demonstrated that cTnI could be found in the nucleus, 11,13,17 and our recently published paper 14 showed that TnI is located in the nuclear of fetal human hearts. We also found that levels of cTnI nucleoprotein in the left ventricle are higher than in the right ventricle.…”

Section: Discussionmentioning

confidence: 88%

“…9 In others and our previous studies, nuclear translocation of cTnI was found in mouse, human fetuses and rat heart tissues. [10][11][12][13][14] Moreover, intranuclear cTnI might regulate the Apt2a2 transcription level through binding with a classic transcription factor YY1, affecting cardiomyocyte contraction and relaxation. 14 However, the potential nuclear localization sequences of cTnI, and more importantly, the role of intranuclear cTnI in cardiac pathological conditions remain unknown and are worth substantial attention.…”

Section: Introductionmentioning

confidence: 99%

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Decreased intranuclear cardiac troponin I impairs cardiac autophagy through FOS/ATG5 in ageing hearts

Liu,

Huang,

et al. 2024

J Cellular Molecular Medi

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In our previous study, intranuclear cardiac troponin I (cTnI) may function as a co‐factor of Yin Yang 1(YY1). Here, we aimed to explore the role of intranuclear cTnI in ageing hearts. Nuclear translocation of cTnI was demonstrated using Western blot and immunofluorescence. The potential nuclear localization sequences (NLSs) of cTnI were predicted by a web server and then verified in 293T cells by putative NLS‐eGFP‐GST and NLS‐mutant transfection. The ratio of Nuclear cTnI/ Total cTnI (Nu/T) decreased significantly in ageing hearts, accompanied with ATG5‐decline‐related impaired cardiac autophagy. RNA sequencing was performed in cTnI knockout hearts. The differential expressed genes (DEGs) were analysed by overlapping with YY1 ChIP‐sequencing data. cTnI gain and loss experiments in vitro determined those filtered DEGs' expression levels. A strong correlation was found between expression patterns cTnI and FOS. Using ChIP‐q‐PCR, we demonstrated that specific binding DNA sequences of cTnI were enriched in the FOS promoter −299 to −157 region. It was further verified that pcDNA3.1 (−)‐cTnI could increase the promoter activity of FOS by using luciferase report assay. At last, we found that FOS can regulate the ATG5 (autophagy‐related gene 5) gene by using a luciferase report assay. Taken together, our results indicate that decreased intranuclear cTnI in ageing hearts may cause impaired cardiac autophagy through the FOS/ATG5 pathway.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Decreased intranuclear cardiac troponin I impairs cardiac autophagy through FOS/ATG5 in ageing hearts

Liu,

Huang,

et al. 2024

J Cellular Molecular Medi

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“…Although cTnI has been reported to present abnormal expression in non-small cell lung cancer tissues and human carcinoma cells (14), its roles in cancers are still unknown. Previously, we demonstrated that cTnI is located in nucleus in adult mouse and human fetal hearts, and found it is associated with the regulation of genes such as PDEs, PGC-1a, ND5 and ATP2A2 (20,25,26). This provides new directions for us to have a closer understanding of the role of gene TNNI3.…”

Section: Discussionmentioning

confidence: 96%

Cardiac-Specific Gene TNNI3 as a Potential Oncogene for Kidney Cancer and Its Involvement in Wnt Signaling Pathway

Zhao

Yang

Chen

et al. 2021

Preprint

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BackgroundCardiac troponin I (cTnI), encoded by TNNI3, is an inhibitory subunit of troponin complex expressed in cardiac muscle and is well known for its central role in the regulation of cardiac contraction. Although its aberrant expression has been reported in non-small cell lung cancer tissues and human carcinoma cells, its roles in cancers are still largely unknown. MethodsIn this work, the mRNA expression profiles of 289 Kidney renal papillary cell carcinoma (KIRP) samples were obtained from The Cancer Genome Atlas (TCGA) database. The tumor samples were classified into TNNI3-low and TNNI3-high groups. A total of 361 differentially expressed genes (DEgenes) were found correlated with TNNI3 expression. Univariate Cox analysis, log-rank test and the least absolute shrinkage and selection operator analysis were used to identify the candidate prognostic genes. The regulatory role of TNNI3 on Wnt signaling pathway was detected by western blot, wound healing assay and cell counting kit-8 assay.ResultsMultivariable Cox regression analysis was performed to establish a prognostic risk formula including genes PTPRH, LGR5 and DMRT3. The low-risk group had a better overall survival than the high-risk group (p < 0.0001), and the areas under the receiver operating characteristic curve for 3- and 5-year overall survival were 0.75 and 0.74, respectively. We thereafter constructed an target gene network to explore the potential functions of the three genes. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis identified their involvement with canonical Wnt signaling and several cancer-related pathways. In wound healing assay, the wound was closed obviously faster in the TNNI3 over-expression group as compared to control and blank groups. Significant increase in cell proliferation was seen at 72 h after transfection with TNNI3 as compared to the control and blank groups.The expressions of LGR5 and β-catenin increased in the TNNI3 over-expression group as compared to control and blank groups.ConclusionCollectively, our data provide evidence that TNNI3 could enhance cell migration and proliferation in 786-O cells and the three-gene signature related to TNNI3 could serve as an independent prognostic biomarker for KIRP. Insights are indeed provided into the potential oncogenic functions of TNNI3 in cancer research.

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“…There were six genes ATP2A2, ITGB4, SGCD, CACNB4, ACTN2 , and TGFB1 associated with both CAD and depression, which are known to be involved in cardiomyopathy (Table S4). Differential expression of ATP2A , which encodes a Ca 2+ pump on the endoplasmic reticulum, is associated with cardiac phenotypes including dilated cardiomyopathy 39,,40 ; and heterozygous conditional knockout mice demonstrate an essential role for ATP2A in neuronal calcium homeostasis resulting in behavioral phenotypes 41 . Similarly, CACNB4 is the one of the most abundant voltage-gated calcium channel subunits expressed in the brain where it is critical for presynaptic signaling, and co-located in the heart where early data suggests it may be involved in cardiac contraction 42–44 .…”

Section: Discussionmentioning

confidence: 99%

Genes associated with depression and coronary artery disease are enriched for inflammation and cardiomyopathy-associated pathways

Singh

Lee

Sealock

et al. 2022

Preprint

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Background: Depression and Coronary Artery Disease (CAD) are highly comorbid conditions. Approximately 40% of individuals who have one diagnosis will also develop the other within their lifetime. Prior research indicates that polygenic risk for depression increases the odds of developing CAD even in the absence of clinical depression. However, the specific genes and pathways involved in comorbid depression-CAD remain unknown. Results: We identified genes that are significantly associated with both depression and CAD, finding that this gene set is enriched for pathways involved in inflammation and previously implicated in cardiomyopathy. We observed increased rate of prevalent, but not incident, cardiomyopathy cases in individuals with comorbid depression-CAD compared to those with CAD alone in three electronic large health record (EHR) datasets. Conclusions: The results of our study implicate genetically regulated inflammatory mechanisms in depression-CAD. Our results also raise the hypothesis that depression-associated CAD may be enriched for cardiomyopathy.

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

Cited by 9 publications

References 35 publications

Decreased intranuclear cardiac troponin I impairs cardiac autophagy through FOS/ATG5 in ageing hearts

Decreased intranuclear cardiac troponin I impairs cardiac autophagy through FOS/ATG5 in ageing hearts

Cardiac-Specific Gene TNNI3 as a Potential Oncogene for Kidney Cancer and Its Involvement in Wnt Signaling Pathway

Genes associated with depression and coronary artery disease are enriched for inflammation and cardiomyopathy-associated pathways

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