Epigenetic hypomethylation and upregulation of matrix metalloproteinase 9 in Kawasaki disease

Kuo, Ho-Chang; Li, Sung‐Chou; Huang, Lien‐Hung; Huang, Ying‐Hsien

doi:10.18632/oncotarget.19650

Cited by 34 publications

(31 citation statements)

References 40 publications

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“…The three active DNA methyltransferases are DNMT1, DNMT3A, and DNMT3B, and three DNA demethylase, TET1-3, have been identified in mammals 7, 8. We have previously shown considerably increased mRNA expressions in toll-like receptors 9, hepcidin 10, 11, matrix metalloproteinases 12, inflammasome sensors of NOD-like receptors 13, and hypomethylation at the gene promoters of these genes, as well as that IVIG treatment can drastically alter these methylation patterns in the WBC cells of KD patients 9-14. Consistently, we have demonstrated that 87.8% of the most of the significant CpG markers between KD patients and controls are hypo-methylation of CpG markers by genome-wide screening on DNA methylation patterns with Illumina HumanMethylation450 (M450K) Bead-Chip microarray assay 15.…”

Section: Introductionmentioning

confidence: 91%

Decreased DNA methyltransferases expression is associated with coronary artery lesion formation in Kawasaki disease

Huang¹,

Chen²,

Lo³

et al. 2019

Int. J. Med. Sci.

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Background: Kawasaki disease (KD) is the most common acute coronary vasculitis to occur in children. Although we have uncovered global DNA hypomethylation in KD, its underlying cause remains uncertain. In this study, we performed a survey of transcript levels of DNA methyltransferases and demethylases in KD patients. Materials and Methods: We recruited 145 participants for this study. The chip studies consisted of 18 KD patients that were analyzed before undergoing intravenous immunoglobulin (IVIG) treatment and at least 3 weeks after IVIG treatment, as well as 36 control subjects, using Affymetrix GeneChip® Human Transcriptome Array 2.0. An additional study of 91 subjects was performed in order to validate real-time quantitative PCR. Results: In our microarray study, the mRNA levels of DNMT1 and DNMT3A were significantly lower while TET2 was higher in acute-stage KD patients compared to the healthy controls. Through PCR validation, we observed that the expression of DNMT1 and TET2 are consistent with the Transcriptome Array 2.0 results. Furthermore, we observed significantly lower DMNT1 mRNA levels following IVIG treatment between those who developed CAL and those who did not. Conclusion: Our findings provide an evidence of DNA methyltransferases and demethylases changes and are among the first report that transient DNA hypomethylation is induced during acute inflammatory phase of Kawasaki disease.

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Section: Introductionmentioning

confidence: 91%

Decreased DNA methyltransferases expression is associated with coronary artery lesion formation in Kawasaki disease

Huang¹,

Chen²,

Lo³

et al. 2019

Int. J. Med. Sci.

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“…We have previously reported that IVIG administration significantly affects methylation pattern alterations in KD patients [17][18][19]. In short, DNA methylation can affect an inactive gene through DNA methyltransferases [20].…”

Section: Introductionmentioning

confidence: 99%

HAMP promoter hypomethylation and increased hepcidin levels as biomarkers for Kawasaki disease

Huang

Kuo

et al. 2018

Journal of Molecular and Cellular Cardiology

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Kawasaki disease (KD) is the most common coronary vasculitis to appear in children with anemia and has been associated with elevated plasma hepcidin levels. We recruited a total of 241 cases, including 18 KD patients, who were tested both prior to receiving intravenous immunoglobulin (IVIG) and at least 3 weeks after IVIG treatment, and 18 febrile controls, who were observed in the Illumina HumanMethylation450 BeadChip study for their CpG markers. The remaining cases consisted of another 92 KD patients and 113 controls that were used for validation by pyrosequencing. We performed a genetic functional study using Luciferase assays. A support vector machine (SVM) classification model was adopted to identify KD patients and control subjects. In this study, KD patients clearly demonstrated a significantly epigenetic hypomethylation of HAMP promoter compared to controls. After receiving IVIG treatment, the hypomethylation status in KD patients was restored, and we observed a significant opposite tendency between the DNA methylation of target CpG sites (cg23677000 and cg04085447) and the hepcidin level. Furthermore, reporter gene assays were used to detect target CpG sites, the methylation of which displayed decreased levels of HAMP gene expression. Of particular note, we developed a SVM classification model with a 90.9% sensitivity, a 91.9% specificity, and 0.94 auROC in the training set. An independent blind cohort also had good performance (96.1% sensitivity and 89.7% specificity). In this study, we demonstrate HAMP promoter hypomethylation, which upregulates hepcidin expression in KD patients. Furthermore, the reliability and robustness of our SVM classification model can accurately serve as KD biomarkers.

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“…More importantly, higher levels of XLOC_006277 transcript were found in patients with KD that later developed CAA. After knockdown of XLOC_006277 with siRNA, KD or CAA-related markers, such as MMP-8 and MMP-9, were down-regulated 32,33 . Therefore, our data support the hypothesis that XLOC_006277 is critical for upstream signals that associate with CAA and is potentially a novel biomarker to predict CAA development.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide transcriptome analysis to further understand neutrophil activation and lncRNA transcript profiles in Kawasaki disease

Chang

Chen

et al. 2019

Sci Rep

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Kawasaki disease (KD) is the most common cause of acquired cardiac disease in children in developed countries. However, little is known regarding the role of transcriptomic targets of KD in the disease progression and development of complications, especially coronary artery aneurysms (CAA). The aim of our study was to identify transcripts affected by KD and their potential role in the disease. We enrolled 37 KD patients and collected blood samples along a comprehensive time-course. mRNA profiling demonstrated an abundance of CD177 transcript in acute KD, and in the intravenous immunoglobulin (IVIG)-resistant group compared to in the IVIG-sensitive group. lncRNA profiling identified XLOC_006277 as the most highly expressed molecule. XLOC_006277 expression in patients at acute stage was 3.3-fold higher relative to patients with convalescent KD. Moreover, XLOC_006277 abundance increased significantly in patients with CAA. XLOC_006277 knockdown suppressed MMP-8 and MMP-9 expression, both associated with heart lesions. Our result suggested that the increase of CD177pos neutrophils was associated with KD. Moreover, this study provided global long non-coding RNA transcripts in the blood of patients with KD, IVIG-resistant KD, or CAA. Notably, XLOC_006277 abundance was associated with CAA, which might contribute to further understanding of CAA pathogenesis in KD.

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Epigenetic hypomethylation and upregulation of matrix metalloproteinase 9 in Kawasaki disease

Cited by 34 publications

References 40 publications

Decreased DNA methyltransferases expression is associated with coronary artery lesion formation in Kawasaki disease

Decreased DNA methyltransferases expression is associated with coronary artery lesion formation in Kawasaki disease

HAMP promoter hypomethylation and increased hepcidin levels as biomarkers for Kawasaki disease

Genome-wide transcriptome analysis to further understand neutrophil activation and lncRNA transcript profiles in Kawasaki disease

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