Oncotarget

Research Papers:

The human blood DNA methylome identifies crucial role of β-catenin in the pathogenesis of Kawasaki disease

Kuang-Den Chen, Ying-Hsien Huang, Mindy Ming-Huey Guo, Tzu-Yang Lin, Wei-Teng Weng, Hsiang-Jen Yang, Kuender D. Yang and Ho-Chang Kuo _

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Oncotarget. 2018; 9:28337-28350. https://doi.org/10.18632/oncotarget.25305

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Abstract

Kuang-Den Chen1,2,*, Ying-Hsien Huang1, Mindy Ming-Huey Guo1, Tzu-Yang Lin2, Wei-Teng Weng2, Hsiang-Jen Yang2, Kuender D. Yang3,4,5 and Ho-Chang Kuo1,*

1Department of Pediatrics and Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

2Institute for Translational Research in Biomedicine, Liver Transplantation Center and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

3Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan

4Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taiwan

5Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan

*These authors have contributed equally to this work

Correspondence to:

Ho-Chang Kuo, email: erickuo48@yahoo.com.tw; dr.hckuo@gmail.com

Kuender D. Yang, email: yangkd.yeh@hotmail.com

Keywords: β-catenin; CD40; CD40 ligand; methylation; Kawasaki disease

Received: January 03, 2018    Accepted: April 16, 2018    Published: June 19, 2018

ABSTRACT

Kawasaki disease (KD) is a type of acute febrile vasculitis syndrome and is the most frequent cause of cardiac illness in children under the age of five years old. Although the etiology of KD remains largely unknown, some recent genome-wide studies have indicated that epigenetic factors may be important in its pathogenesis.

We enrolled 24 KD patients and 24 non-KD controls in this study to access their DNA methylation status using HumanMethylation450 BeadChips. Another 34 KD patients and 62 control subjects were enrolled for expression validation. Of the 3193 CpG methylation regions with a methylation difference ≥ 20% between KD and controls, 3096 CpG loci revealed hypomehtylation, with only 3% being hypermethylated. Pathway buildup identified 11 networked genes among the hypermethylated regions, including four transcription factors: nuclear factor of activated T-cells 1, v-ets avian erythroblastosis virus E26 oncogene homolog 1, runt related transcription factor 3, and retinoic acid receptor gamma, as well as the activator β-catenin. Ten of these network-selected genes demonstrated a significant decrease in mRNA in KD patients, whereas only CTNNB1 significantly decreased in correlation with coronary artery lesions in KD patients. Furthermore, CTNNB1-silenced THP-1 monocytic cells drastically increased the expression of CD40 and significantly increased the expression of both CD40 and CD40L in cocultured human coronary artery endothelial cells.

This study is the first to identify network-based susceptible genes of hypermethylated CpG loci, their expression levels, and the functional impact of β-catenin, which may be involved in both the cause and the development of KD.


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