Inhibition of Gata4 and Tbx5 by Nicotine-Mediated DNA Methylation in Myocardial Differentiation

Jiang, Xiyi; Yuan, Feng; Ye, Li Tong; Li, Xiao Hong; Feng, Juan; Zhang, Meng Zhen; Shelat, Harnath; Wassler, Michael; Li, Yangxin; Geng, Yong–Jian; Yu, Xi

doi:10.1016/j.stemcr.2016.12.016

Cited by 28 publications

(23 citation statements)

References 45 publications

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“…GATA4 is well known for its central role in embryogenesis [7], and in myocardial differentiation and function [8]. Besides, this protein is thought to be necessary for testicular development [9].…”

Section: Introductionmentioning

confidence: 99%

Acetylation of GATA4 on Lysine Residue K313 Promotes Osteoblastic Cells Growth

You¹,

Song²,

Wang³

2018

Cell Physiol Biochem

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Background/Aims: GATA4, a protein related to osteoblast differentiation and mineralization, whose acetylation is essential for cardiac defects. Here, we aimed to explore the functional impacts of GATA4 acetylation on osteoporosis (OS). Methods: GATA4 acetylation in hFOB1.19 and 293T cells was detected after exposure of HDAC inhibitors (TSA and SAHA). Co-immunoprecipitation was conducted to determine which HATs and HDACs was involved in the modulation of GATA4 acetylation/deacetylation, and to identify the acetylation site. The transcriptional activity of GATA4 was measured in the presence or absence of cycloheximide. Furthermore, hFOB1.19 cells viability and apoptosis were evaluated after transfection with acetylation-defective mutant of GATA4. Results: As a result, GATA4 acetylation was identified as a pivotal event in hFOB1.19 cells. GATA4 can be acetylated by P300/CBP, and the acetylation site was on lysine residue K313. Besides, the acetylation of GATA4 can be impaired by HDAC1, rather than by HDAC2-5. GATA4 acetylation contributed to the stability and transcription of GATA4. Moreover, GATA4 acetylation activated CCND2 transcription, and mutation of GATA4 on K-313 reduced cell viability and increased a mitochondria-dependent apoptosis in hFOB1.19 cells. Conclusion: Our data suggest that GATA4 exists as an acetylated protein in hFOB1.19 cells. Acetylation regulates the stability and transcription of GATA4, and activates CCND2 transcription, which may explain the growth-promoting functions of GATA4 in hFOB1.19 cells.

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Section: Introductionmentioning

confidence: 99%

Acetylation of GATA4 on Lysine Residue K313 Promotes Osteoblastic Cells Growth

You¹,

Song²,

Wang³

2018

Cell Physiol Biochem

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“…Disruption of any of the proteins or their interactions can result in atrial or ventricular septal defects . Another previous study showed that nicotine directly suppresses myocardial differentiation by regulating the expression of cardiac genes such as Gata4 and Tbx5 via promoter of DNA hypermethylation, thereby contributing to the cause of cardiac defect associated with smoking . Mutation of HAND1 has been shown to hinder the effects of GATA4, another vital cardiac transcription factor, and is associated with congenital heart disease .…”

Section: Discussionmentioning

confidence: 99%

Effects of cigarette smoke components on myocardial differentiation of mouse embryonic stem cells

Kim

et al. 2019

Environmental Toxicology

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The heart is the first organ formed in the developing fetus, and abnormal development of the heart is a major cause of fetal death. The adverse effects of cigarette smoke on the heart have been well established, but it is not well understood how cigarette smoke components regulate signaling molecules and cardiac specific functions during the early differentiation stage of the embryonic heart. In this study, we identified changes in the size of mouse embryoid bodies (mEBs) in response to treatment with cigarette smoke extract (CSE) via regulation of HDAC2, p53, p21, and cyclin D1 protein expression, which are cardiac differentiation and cell-cycle markers, respectively.In addition, exposure of mouse embryonic stem cells (mESCs) to cigarette smoke components inhibited myocardial differentiation and development through the expression of HDAC1, HDAC2, GATA4, NKX2-5, TBX5, HAND1, and Troponin I. Long-term exposure studies showed that CSE and nicotine may delay the development of mouse cardiomyocytes from mESCs and inhibit the contractibility, which is a fundamental function of the heart. Taken together, these findings suggest that cigarette smoke components, including nicotine, may affect abnormal myocardial differentiation and development. K E Y W O R D S cardiomyocyte, cell cycle, cigarette smoke extract, HDACs, mouse embryonic stem cells, myocardial differentiation, nicotine 1 | INTRODUCTION Embryonic stem cells isolated from the inner cell mass in the blastocyst stage can differentiate into three germ layers, the endoderm, mesoderm, and ectoderm. 1 The mesoderm layer forms connective tissues and muscles including cardiac muscle throughout the body. The heart is the first organ formed and differentiated in the developing embryo and fetus. 2,3 In early embryonic development, cardiac cells begin to develop through specific protein signaling. During embryogenesis, NK2 homeobox 5 (NKX2-5) is expressed in early cardiac mesoderm cells throughout the left ventricle and atrial chambers. 4,5 NKX2-5 activates a number of downstream transcription factors (such as myocyte enhancer factor-2 [MEF2] and GATA), which activate the expression of cardiac muscle specific proteins. Mutations in NKX2-5 result in heart development defects and congenital heart malformations. 6-8 The heart tube undergoes right-ward looping to change from anterior/posterior polarity to left/right polarity. 9 Looping alsodepends on heart specific proteins activated by NKX2-5 such as heartand neural crest derivatives-expressed protein (HAND) 1 and HAND2. 10,11 HAND1 is localized to the left ventricle while HAND2 is localized to the right ventricle. 12 When the heart is developed through this specific protein signaling, it starts to beat and pump blood at about 22-23 days, with blood flow beginning in week 4. 2,3 It is well known that cigarette smoke adversely affects the development of early embryos. [13][14][15] Cigarette smoke contains over 4000

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“…Nevertheless, the idea that early life, including early (in utero) exposure to environmental factors, such as nicotine, hormones, and nutrients, influences development, with long-lasting effects on organ and tissue function (a phenomenon called developmental programming (43,44)), also has major implications for our understanding of CVD development and progression. In mammals, DNA demethylation in the parental gametes occurs by both active demethylation by translocation (TET) proteins and passive loss of methylation during subsequent cell divisions (4).…”

Section: The Evidence For Transgenerational Epigenetic Inheritancementioning

confidence: 99%

“…Experiments in animals show that nicotinic stimulation of acetylcholine receptors inhibits myocardial differentiation by down-regulation of Tbx5 and Gata4 in both differentiating embryonic bodies and in the offspring’s heart, and this is accompanied by promoter hypermethylation (44). Physical exercise influences the DNA methylation profile of adipose tissue in apparently healthy individuals, including at a number of genes implicated in the development of type 2 diabetes (62).…”

Section: Dna Methylationmentioning

confidence: 99%

“…Among ncRNAs, miRNAs represent the most broadly-studied species, and are reported to be involved in cardiogenesis, vascular and blood development, and a plethora of CVDs and conditions (79). Among those miRNAs studied in genetic and pharmacological deletion models and most intensively considered for therapeutic development approaches are miR-133, miR-132, and miR-199b, which regulate various prohypertrophic intracellular signaling cascades and autophagy in heart muscle cells; the muscle-specific miRNAs (myomiRs) miR-208a, miR-208b, and miR-499, which are embedded in myosin genes and are responsible for cardiac muscle contractions; miR-21, which regulates extracellular signal-related kinase (ERK)–mitogen-activated protein kinase (MAPK) signaling in fibroblasts and controls cardiac fibrosis; and miR-92, which is involved in angiogenesis and functional recovery in ischemic heart conditions (44,80). …”

Section: Noncoding Rnamentioning

confidence: 99%

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Translational Perspective on Epigenetics in Cardiovascular Disease

Harst

Windt

Chambers

2017

Journal of the American College of Cardiology

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A plethora of environmental and behavioral factors interact, resulting in changes in gene expression and providing a basis for the development and progression of cardiovascular diseases. Heterogeneity in gene expression responses among cells and individuals involves epigenetic mechanisms. Advancing technology allowing genome-scale interrogation of epigenetic marks provides a rapidly-expanding view of the complexity and diversity of the epigenome. In this review, we discuss the expanding landscape of epigenetic modifications and highlight their importance for our future understanding of disease. The epigenome provides a mechanistic link between environmental exposures and gene expression profiles ultimately leading to disease. We discuss the current evidence for transgenerational epigenetic inheritance and summarize the data linking epigenetics to cardiovascular disease. Furthermore, we review the potential targets provided by the epigenome for the development of future diagnostics, preventive strategies, and therapy for cardiovascular disease. Finally, we provide some suggestions for future directions.

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Inhibition of Gata4 and Tbx5 by Nicotine-Mediated DNA Methylation in Myocardial Differentiation

Cited by 28 publications

References 45 publications

Acetylation of GATA4 on Lysine Residue K313 Promotes Osteoblastic Cells Growth

Acetylation of GATA4 on Lysine Residue K313 Promotes Osteoblastic Cells Growth

Effects of cigarette smoke components on myocardial differentiation of mouse embryonic stem cells

Translational Perspective on Epigenetics in Cardiovascular Disease

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