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Title: DNA methyltransferase 3B plays a protective role against hepatocarcinogenesis caused by chronic inflammation via maintaining mitochondrial homeostasis
Authors: Iguchi, Eriko
Takai, Atsushi  kyouindb  KAKEN_id
Takeda, Haruhiko
Kumagai, Ken
Arasawa, Soichi
Eso, Yuji  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0003-4426-1491 (unconfirmed)
Shimizu, Takahiro
Ueda, Yoshihide
Marusawa, Hiroyuki
Seno, Hiroshi
Author's alias: 井口, 恵里子
髙井, 淳
竹田, 治彦
熊谷, 健
荒澤, 壮一
惠莊, 裕嗣
清水, 孝洋
上田, 佳秀
丸澤, 宏之
妹尾, 浩
Keywords: DNA methylation
Hepatitis
Hepatocellular carcinoma
Mitochondria
Issue Date: 4-Dec-2020
Publisher: Springer Nature
Journal title: Scientific Reports
Volume: 10
Thesis number: 21268
Abstract: Most hepatocellular carcinomas (HCCs) develop on the basis of chronic hepatitis, but the mechanism of epigenetic regulation in inflammatory hepatocarcinogenesis has yet to be elucidated. Among de novo DNA methyltransferases (DNMTs), DNMT3B has lately been reported to act specifically on actively transcribed genes, suggesting the possibility that it plays a role in the pathogenesis of cancer. We confirmed that DNMT3B isoforms lacking its catalytic domain were highly expressed in HCCs compared with non-tumorous liver tissue. To elucidate the role of DNMT3B in hepatocarcinogenesis, we generated a genetically engineered mouse model with hepatocyte-specific Dnmt3b deletion. The liver of the Dnmt3b-deficient mice exhibited an exacerbation of thioacetamide-induced hepatitis, progression of liver fibrosis and a higher incidence of HCC compared with the liver of the control mice. Whole-genome bisulfite sequencing verified a lower CG methylation level in the Dnmt3b-deficient liver, demonstrating differentially methylated regions throughout the genome. Transcriptome analysis revealed decreased expression of genes related to oxidative phosphorylation in the Dnmt3b-deficient liver. Moreover, primary hepatocytes isolated from the Dnmt3b-deficient mice showed reduced mitochondrial respiratory capacity, leading to the enhancement of oxidative stress in the liver tissue. Our findings suggest the protective role of DNMT3B against chronic inflammation and HCC development via maintaining mitochondrial homeostasis.
Rights: © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
URI: http://hdl.handle.net/2433/259443
DOI(Published Version): 10.1038/s41598-020-78151-2
PubMed ID: 33277576
Appears in Collections:Journal Articles

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