Basic Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 21, 2021; 27(43): 7530-7545
Published online Nov 21, 2021. doi: 10.3748/wjg.v27.i43.7530
Genome-wide map of N6-methyladenosine circular RNAs identified in mice model of severe acute pancreatitis
Jun Wu, Xiao-Hui Yuan, Wen Jiang, Yi-Chen Lu, Qi-Lin Huang, Yi Yang, Hua-Ji Qie, Jiang-Tao Liu, Hong-Yu Sun, Li-Jun Tang
Jun Wu, Xiao-Hui Yuan, Wen Jiang, Yi-Chen Lu, Qi-Lin Huang, Yi Yang, Hua-Ji Qie, Jiang-Tao Liu, Hong-Yu Sun, Li-Jun Tang, Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu 610036, Sichuan Province, China
Jun Wu, Xiao-Hui Yuan, Wen Jiang, Yi-Chen Lu, Hua-Ji Qie, Jiang-Tao Liu, Hong-Yu Sun, Li-Jun Tang, College of Medicine, Southwest Jiaotong University, Chengdu 610036, Sichuan Province, China
Hong-Yu Sun, Laboratory of Basic Medicine, The General Hospital of Western Theater Command, Chengdu 610036, Sichuan Province, China
Author contributions: Wu J and Yuan XH contributed equally to this work; Tang LJ and Sun HY participated in the study conception and design; Wu J and Yuan XH participated in the writing of the main manuscript; Wu J, Yuan XH, Jiang W and Lu YC participated in the performance of the experiments; Huang QL and Yang Y participated in statistical data analysis and interpretation; Qie HJ and Liu JT participated in the preparation of figures; Tang LJ and Sun HY participated in the revision of the manuscript and final approval.
Supported by the National Natural Science Foundation of China, No. 81772001; and the National Clinical Key Subject of China, No. 41732113.
Institutional review board statement: The study was reviewed and approved by the Institutional Ethics Committee at the General Hospital of Western Theater Command (Chengdu, China), No. A20190252005.
Institutional animal care and use committee statement: The experimental procedures were reviewed and approved by the Institutional Animal Care and Use Committee at the General Hospital of Western Theater Command (Chengdu, China), and were conducted in accordance with the established International Guiding Principles for Animal Research.
Conflict-of-interest statement: The authors declare that there is no conflict of interest related to this study.
Data sharing statement: We had submitted the data to the online repository, which can be found at: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE173298.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Li-Jun Tang, MD, PhD, Chief Doctor, Professor, Department of General Surgery and Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, No. 270 Tianhuan Road, Furong Avenue, Jinniu District, Chengdu 610036, Sichuan Province, China. tanglj2016@163.com
Received: May 19, 2021
Peer-review started: May 19, 2021
First decision: June 22, 2021
Revised: June 23, 2021
Accepted: September 15, 2021
Article in press: September 15, 2021
Published online: November 21, 2021
Abstract
BACKGROUND

Severe acute pancreatitis (SAP) is a deadly inflammatory disease with complex pathogenesis and lack of effective therapeutic options. N6-methyladenosine (m6A) modification of circRNAs plays important roles in physiological and pathological processes. However, the roles of m6A circRNA in the pathological process of SAP remains unknown.

AIM

To identify transcriptome-wide map of m6A circRNAs and to determine their biological significance and potential mechanisms in SAP.

METHODS

The SAP in C57BL/6 mice was induced using 4% sodium taurocholate salt. The transcriptome-wide map of m6A circRNAs was identified by m6A-modified RNA immunoprecipitation sequencing. The biological significance of circRNAs with differentially expressed m6A peaks was evaluated through gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis. The underlying mechanism of m6A circRNAs in SAP was analyzed by constructing of m6A circRNA-microRNA networks. The expression of demethylases was determined by quantitative polymerase chain reaction and western blot to deduce the possible mechanism of reversible m6A process in SAP.

RESULTS

Fifty-seven circRNAs with differentially expressed m6A peaks were identified by m6A-modified RNA immunoprecipitation sequencing, of which 32 were upregulated and 25 downregulated. Functional analysis of these m6A circRNAs in SAP found some important pathways involved in the pathogenesis of SAP, such as regulation of autophagy and protein digestion. In m6A circRNA–miRNA networks, several important miRNAs participated in the occurrence and progression of SAP were found to bind to these m6A circRNAs, such as miR-24-3p, miR-26a, miR-92b, miR-216b, miR-324-5p and miR-762. Notably, the total m6A level of circRNAs was reduced, while the demethylase alkylation repair homolog 5 was upregulated in SAP.

CONCLUSION

m6A modification of circRNAs may be involved in the pathogenesis of SAP. Our findings may provide novel insights to explore the possible pathogenetic mechanism of SAP and seek new potential therapeutic targets for SAP.

Keywords: Severe acute pancreatitis, Circular RNAs, N6-methyladenosine, MeRIP-seq, Epigenetic analysis

Core Tip: We identified a transcriptome-wide map of N6-methyladenosine (m6A) circRNAs and determined their biological significance and potential mechanisms in severe acute pancreatitis (SAP). The main findings were: (1) Function analysis found that circRNAs with differentially expressed m6A peaks were involved in the key process of SAP; (2) m6A may affect the interplays of circRNAs and microRNAs to participate in the pathogenesis of SAP; and (3) Demethylase alkylation repair homolog 5 may play key roles in dynamic process of m6A to downregulate the total m6A level of circRNAs in SAP. We provided novel insights to explore the possible pathophysiological mechanism of SAP and seek new potential therapeutic targets.