Liver-specific Mettl3 ablation delays liver regeneration in mice

Jiaxiang Meng; Zhicong Zhao; Zhifeng Xi; Qiang Xia

doi:10.1016/j.gendis.2020.11.002

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Liver-specific Mettl3 ablation delays liver regeneration in mice

Full-length article | 更新时间：2022-06-24

- Liver-specific Mettl3 ablation delays liver regeneration in mice
- Liver-specific Mettl3 ablation delays liver regeneration in mice
- Genes & Diseases 2022年9卷第3期
- 作者机构：
  
  Department of Liver Surgery and Liver Transplantation Center, Renji Hospital, School of Medicine, Shanghai Jiaotong University,Shanghai,PR China,200127
- 作者简介：
- 基金信息：
- DOI：10.1016/j.gendis.2020.11.002
  中图分类号：
- 纸质出版日期：2022，
  
  网络出版日期：2022-5-1，
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Jiaxiang Meng, Zhicong Zhao, Zhifeng Xi, 等. Liver-specific Mettl3 ablation delays liver regeneration in mice[J]. Genes & Diseases, 2022,9(3).

Jiaxiang Meng, Zhicong Zhao, Zhifeng Xi, et al. Liver-specific Mettl3 ablation delays liver regeneration in mice[J]. Genes & Diseases, 2022,9(3).
Jiaxiang Meng, Zhicong Zhao, Zhifeng Xi, 等. Liver-specific Mettl3 ablation delays liver regeneration in mice[J]. Genes & Diseases, 2022,9(3). DOI： 10.1016/j.gendis.2020.11.002.

Jiaxiang Meng, Zhicong Zhao, Zhifeng Xi, et al. Liver-specific Mettl3 ablation delays liver regeneration in mice[J]. Genes & Diseases, 2022,9(3). DOI： 10.1016/j.gendis.2020.11.002.

摘要

Abstract

This study investigated the role of N6-methyladenosine RNA methylation in liver regeneration following partial hepatectomy in mice. We created a liver-specific knockout mouse model by the deletion of Mettl3

a key component of the N6-methyladenosine methyltransferase complex

using the albumin-Cre system. Mettl3 liver-specific knockout mice and their wild-type littermates were subjected to 2/3 partial hepatectomy. Transcriptomic changes in liver tissue at 48 h after partial hepatectomy were detected by RNA-seq. Immunohistochemistry and immunofluorescence were used to determine protein expression levels of Ki67

hepatocyte nuclear factor 4 alpha

and cytokeratin 19. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling was also performed. Liver weight/body weight ratios after partial hepatectomy were significantly lower in Mettl3 liver-specific knockout mice than in wild-type mice at 48 h after 2/3 partial hepatectomy (3.1% ± 0.11%

vs.

2.7% ± 0.03%). Compared with wild-type littermates

Mettl3 liver-specific knockout mice showed reduced bromodeoxyuridine staining and reduced Ki-67 expression at 48 h after 2/3 partial hepatectomy. RNA-seq analysis showed that Mettl3 liver-specific knockout delayed the cell cycle progression in murine liver by downregulating the expression levels of genes encoding cyclins D1

and B2. Loss of Mettl3-mediated N6-methyladenosine function led to attenuated liver regeneration by altering the mRNA decay of suppressor of cytokine signaling 6

thereby inhibiting the phosphorylation of signal transducer and activator of transcription 3 during early liver regeneration. These results demonstrated the importance of N6-methyladenosine mRNA modification in liver regeneration and suggest that Mettl3 targeting might facilitate liver regeneration.

关键词

Keywords

Liver regenerationMETTL3N6-methyladenosineSocs6STAT3

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