Exploration of the Effect on Genome-Wide DNA Methylation by miR-143 Knock-Out in Mice Liver.

Xingping Chen,Yongliang Zhang,Jiajie Sun,Qianyun Xi,Jie Liu,Junyi Luo,Ting Chen

doi:10.3390/ijms222313075

Xingping Chen, Yongliang Zhang + Show 5 more

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https://doi.org/10.3390/ijms222313075

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Abstract

MiR-143 play an important role in hepatocellular carcinoma and liver fibrosis via inhibiting hepatoma cell proliferation. DNA methyltransferase 3 alpha (DNMT3a), as a target of miR-143, regulates the development of primary organic solid tumors through DNA methylation mechanisms. However, the effect of miR-143 on DNA methylation profiles in liver is unclear. In this study, we used Whole-Genome Bisulfite Sequencing (WGBS) to detect the differentially methylated regions (DMRs), and investigated DMR-related genes and their enriched pathways by miR-143. We found that methylated cytosines increased 0.19% in the miR-143 knock-out (KO) liver fed with high-fat diet (HFD), compared with the wild type (WT). Furthermore, compared with the WT group, the CG methylation patterns of the KO group showed lower CG methylation levels in CG islands (CGIs), promoters and hypermethylation in CGI shores, 5′UTRs, exons, introns, 3′UTRs, and repeat regions. A total of 984 DMRs were identified between the WT and KO groups consisting of 559 hypermethylation and 425 hypomethylation DMRs. Furthermore, DMR-related genes were enriched in metabolism pathways such as carbon metabolism (serine hydroxymethyltransferase 2 (Shmt2), acyl-Coenzyme A dehydrogenase medium chain (Acadm)), arginine and proline metabolism (spermine synthase (Sms), proline dehydrogenase (Prodh2)) and purine metabolism (phosphoribosyl pyrophosphate synthetase 2 (Prps2)). In summary, we are the first to report the change in whole-genome methylation levels by miR-143-null through WGBS in mice liver, and provide an experimental basis for clinical diagnosis and treatment in liver diseases, indicating that miR-143 may be a potential therapeutic target and biomarker for liver damage-associated diseases and hepatocellular carcinoma.

Highlights

MiR-143-encoding genes are highly conserved and located on the fifth autosome [1].MicroRNAs are endogenous short single-stranded non-coding RNA molecules, found in eukaryotic cells, that range in lengths from 18 to 25 nt [2,3]
MiRNAs have been found to play a crucial role in the regulation of all major cellular functions, including cell proliferation, differentiation, and apoptosis, which are involved in various human diseases [4]
The results showed that differentially methylated regions (DMRs) were mainly distributed in the CG islands (CGIs), exons and introns

Summary

Introduction

MiR-143-encoding genes are highly conserved and located on the fifth autosome [1].MicroRNAs (miRNAs) are endogenous short single-stranded non-coding RNA molecules, found in eukaryotic cells, that range in lengths from 18 to 25 nt [2,3]. MiRNAs have been found to play a crucial role in the regulation of all major cellular functions, including cell proliferation, differentiation, and apoptosis, which are involved in various human diseases [4]. MiR-143 is widely distributed in mammalian tissues and serves an important role in a number of physiological processes, such as adipocyte and smooth muscle differentiation [5,6,7], tumorigenesis suppression [8], DNA methylation [9,10,11,12] and development of tissues and organs [13]. MiRNA degrades the target mRNA, or inhibits its translation, by combining with the seed region in the 30 UTR of the target mRNA, being able to regulate physiological or biochemical processes [16]

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