microRNA-152 Mediates DNMT1-Regulated DNA Methylation in the Estrogen Receptor α Gene

Wang, Yung Song; Chou, Wen Wen; Chen, Ku Chung; Cheng, Hsin Yun; Lin, Ruey Tay; Juo, Suh Hang Hank

doi:10.1371/journal.pone.0030635

Cited by 71 publications

(52 citation statements)

References 41 publications

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“…Thus miR148a could downregulate DNMT expression, which decreased the methylation of RUNX3, and RUNX3 protein levels increased. Our findings are consistent with several studies that provide evidence for miRNA-induced regulation of promoter methylation through DNMTs (Braconi et al, 2010;Garzon et al, 2009;Li et al, 2012;Pan et al, 2010;Wang et al, 2012;Zhao et al, 2011).…”

Section: Discussionsupporting

confidence: 93%

MicroRNA-148a Can Regulate Runt-Related Transcription Factor 3 Gene Expression via Modulation of DNA Methyltransferase 1 in Gastric Cancer

Zuo

Xia

et al. 2013

Molecules and Cells

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Underexpression of the gene runt-related transcription factor 3 (RUNX3), an important tumor suppressor, is known to contribute to gastric cancer progression. However, the mechanism underlying aberrant RUNX3 expression has not been fully elucidated. We investigated the role of microRNA-148a (miR-148a) and DNA methyltransferases (DNMTs) in RUNX3 promoter methylation and gene expression. RUNX3 mRNA, RUNX3 protein, and methylation levels were assayed in human gastric cancer tissues and matched normal tissues, and AGS and BGC-823 cells by real-time reverse transcription PCR, Western blot, and methylation-specific PCR, respectively. A correlation between RUNX3 mRNA levels and that of miR-148a was also investigated in gastric cancer tissues. We found that RUNX3 mRNA levels were significantly downregulated in gastric cancer tissues compared with their matched normal tissues, and were closely associated with miR-148a expression. After treatment of human gastric cancer AGS and BGC-823 cells with the DNA methylation inhibitor 5-aza-2'-deoxycytidine, a significant increase in RUNX3 mRNA, RUNX3 protein, and the non-methylated form of the RUNX3 promoter were observed relative to untreated cells. Enforced expression of miR-148a, which can modulate DNMT1 and DNMT3B, also increased the expression of RUNX3 in gastric cancer cells. Knockdown of DNMT1 was associated with increased levels of RUNX3 mRNA and RUNX3 protein, while knockdown of DNMT3B did not have any effect on these in BGC-823 cells. Our results show that miR-148a may regulate RUNX3 expression through modulation of DNMT1-dependent DNA methylation in gastric cancer and highlight a miRNA-epigenetics regulation mechanism of gene expression.

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Section: Discussionsupporting

confidence: 93%

MicroRNA-148a Can Regulate Runt-Related Transcription Factor 3 Gene Expression via Modulation of DNA Methyltransferase 1 in Gastric Cancer

Zuo

Xia

et al. 2013

Molecules and Cells

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“…Because DNMT1, DNMT3a, and DNMT3b are the principal mediators of DNA methylation in mammalian cells, 26,27 we determined the expression of DNMT proteins in atherosclerotic plaques. In the serial sections of aortic sinus stained with α-smooth muscle actin or F4/80 and immunofluorescence images, we found that DNMT1 was predominantly expressed in VSMCs, rather than in macrophages, in the plaque of ApoE −/− mice ( Figure 2C and 2D).…”

Section: Dnmt Inhibition Dynamically Regulated Dna Methylation and Tementioning

confidence: 99%

The Yin–Yang Dynamics of DNA Methylation Is the Key Regulator for Smooth Muscle Cell Phenotype Switch and Vascular Remodeling

Zhuang

Luan

et al. 2017

ATVB

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A therosclerosis is a chronic and multifactorial disease mediated by complex interplay between resident endothelial cells, vascular smooth muscle cells (VSMCs), and infiltrating macrophages. Environmental exposure to risk factors such as hyperlipidemia throughout the development of atherosclerosis causes vascular remodeling and in turn reduces arterial compliance. Although many drugs inhibiting vascular remodeling and metabolic disorder offer an effective therapeutic strategy for preventing atherosclerotic progression, none of these drugs are found to totally reverse atherosclerotic plaque in animal experiments.1,2 Furthermore, clinical trials have revealed that intensive lipid-lowering treatment with rosuvastatin or atorvastatin only leads to limited plaque regression (1.22% and 0.99%, respectively), 3,4 although routine statin treatments can significantly reduce >30% of the risk of major adverse cardiac events such as myocardial infarction. [5][6][7][8][9] The memory effects of atherosclerosis imply that the mechanisms for atherogenesis are partially independent of the risk factors. It seems that atherosclerosis would progress at its own pace, once the atherosclerotic plaques are formed. Epigenetic modifications refer to heritable changes in gene expression that are not coded in the DNA sequence itself. Studies demonstrate that epigenomic changes in tissues and cells play important roles in vascular remodeling and atherosclerosis.10 DNA methylation is the most understood epigenetic modification. The effect of DNA methylation on gene expression can persist even if the risk factors are removed. In eukaryotic genomes, DNA methyltransferases (DNMTs) catalyze the conversion of cytosines, predominantly in cytidine phosphate guanosine (CpG) dinucleotides, to 5-methylcytosine (5-mC), and then silence gene expression. The DNMT inhibitor 5-aza-2′-deoxycytidine (5-aza) is © 2016 American Heart Association, Inc. Objective-DNA methylation plays an important role in chronic diseases such as atherosclerosis, yet the mechanisms are poorly understood. The objective of our study is to indicate the regulatory mechanisms of DNA methylation in vascular smooth muscle cells (VSMCs) and its roles in atherosclerosis. Approach and Results-In ApoE −/− mice fed a Western diet, DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine, significantly attenuated atherosclerotic lesions (20.1±2.2% versus 30.8±7.5%; P=0.016) and suppressed DNA methyltransferase activity and concomitantly decreased global 5-methylcytosine content in atherosclerotic lesions of ApoE −/− mice. Using a carotid ligation model, we found that 5-aza-2′-deoxycytidine also dramatically inhibited neointimal formation (intimal area: 2.25±0.14×10 4 versus 4.07±0.22×10 4 μm 2 ; P<0.01). Abnormal methylation status at the promoter of ten-eleven translocation 2, one of the key demethylation enzymes in mammals, was ameliorated after 5-aza-2′-deoxycytidine treatment, which in turn caused an increase in global DNA hydroxymethylation and 5-hydroxymethylcytosine enrichment at the p...

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“…miR-NA-29b can reduce the expression of DNMT enzymes and thereby affect the global methylation status (45). Wang et al demonstrated that miRNA-152 can knockdown DNMT1 in human aortic SMCs, leading to hypermethylation of the ER-a gene (135). HDAC expression can be regulated by miRNAs, such as miRNA-449a (97).…”

Section: Rna Interferencementioning

confidence: 99%

The Role of Redox Signaling in Epigenetics and Cardiovascular Disease

Kim

Ryan²,

Archer³

2013

Antioxidants & Redox Signaling

108

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Significance: The term epigenetics refers to the changes in the phenotype and gene expression that occur without alterations in the DNA sequence. There is a rapidly growing body of evidence that epigenetic modifications are involved in the pathological mechanisms of many cardiovascular diseases (CVDs), which intersect with many of the pathways involved in oxidative stress. Recent Advances: Most studies relating epigenetics and human pathologies have focused on cancer. There has been a limited study of epigenetic mechanisms in CVDs. Although CVDs have multiple established genetic and environmental risk factors, these explain only a portion of the total CVD risk. The epigenetic perspective is beginning to shed new light on how the environment influences gene expression and disease susceptibility in CVDs. Known epigenetic changes contributing to CVD include hypomethylation in proliferating vascular smooth muscle cells in atherosclerosis, changes in estrogen receptor-a (ER-a) and ER-b methylation in vascular disease, decreased superoxide dismutase 2 expression in pulmonary hypertension (PH), as well as trimethylation of histones H3K4 and H3K9 in congestive heart failure. Critical Issues: In this review, we discuss the epigenetic modifications in CVDs, including atherosclerosis, congestive heart failure, hypertension, and PH, with a focus on altered redox signaling. Future Directions: As advances in both the methodology and technology accelerate the study of epigenetic modifications, the critical role they play in CVD is beginning to emerge. A fundamental question in the field of epigenetics is to understand the biochemical mechanisms underlying reactive oxygen species-dependent regulation of epigenetic modification.

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microRNA-152 Mediates DNMT1-Regulated DNA Methylation in the Estrogen Receptor α Gene

Cited by 71 publications

References 41 publications

MicroRNA-148a Can Regulate Runt-Related Transcription Factor 3 Gene Expression via Modulation of DNA Methyltransferase 1 in Gastric Cancer

MicroRNA-148a Can Regulate Runt-Related Transcription Factor 3 Gene Expression via Modulation of DNA Methyltransferase 1 in Gastric Cancer

The Yin–Yang Dynamics of DNA Methylation Is the Key Regulator for Smooth Muscle Cell Phenotype Switch and Vascular Remodeling

The Role of Redox Signaling in Epigenetics and Cardiovascular Disease

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