N<sup>6</sup>-甲基腺嘌呤甲基化在肝脏疾病中的作用

马艳珍; 吴芙蓉; 张家富; 凡畅; 黄少鹏; 陈森; 姜辉

doi:10.3969/j.issn.1001-5256.2021.11.051

N⁶-甲基腺嘌呤甲基化在肝脏疾病中的作用

DOI: 10.3969/j.issn.1001-5256.2021.11.051

1.
安徽中医药大学第一附属医院临床研究实验中心，合肥 230031
2.
中国科学技术大学附属第一医院药剂科，合肥 230001

基金项目:

国家自然科学基金项目 (81973648)

详细信息

通信作者:
姜辉，jhanbing@163.com

中图分类号: R575
计量
- 文章访问数: 465
- HTML全文浏览量: 153
- PDF下载量: 40
- 被引次数: 0
出版历程
- 收稿日期: 2021-04-15
- 录用日期: 2021-06-07
- 出版日期: 2021-11-20

Role of N⁶-methyladenosine methylation in liver diseases

1.
Clinical Research Center, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei 230031, China
2.
Department of Pharmacy, The First Affiliated Hospital of University of Science and Technology of China, Hefei 230001, China

Research funding:

National Natural Science Foundation of China (81973648)

摘要

摘要: N⁶-甲基腺嘌呤(m6A)是存在于多种RNAs中的化学修饰方式，最常见于mRNA。肝脏是机体重要的代谢和消化器官，m6A甲基化在肝脏生理病理过程中发挥着重要作用。简述了m6A甲基化在肝脏生理和病毒性肝炎、非酒精性脂肪性肝病、肝纤维化以及肝细胞癌等肝脏疾病中的生物学作用及潜在应用价值，指出m6A甲基化可调控相关因子，参与肝脏疾病的发生发展，为其临床诊疗提供新的思路和靶点。
- N⁶-甲基腺嘌呤 /
- 肝疾病 /
- 甲基化
Abstract: N⁶-methyladenosine (m6A) is a chemical modification that exists in a variety of RNAs and is most commonly observed in mRNA. The liver is a vital metabolic and digestive organ in human body, and m6A methylation plays an important role in the physiological and pathological processes of the liver. This article reviews the biological role and potential application value of m6A methylation in liver physiology and liver diseases such as viral hepatitis, nonalcoholic fatty liver disease, liver fibrosis, and hepatocellular carcinoma, and it is pointed out that m6A methylation can regulate related factors and is involved in the development and progression of liver diseases, which provides new ideas and targets for clinical diagnosis and treatment.
- N⁶-methyladenosine /
- Liver Diseases /
- Methylation

HTML全文

图 1 m6A甲基化参与肝脏病理生理功能的调控

注：NAFLD，非酒精性脂肪性肝病；HCC，肝细胞癌。

下载: 全尺寸图片幻灯片

参考文献(39)

[1]	HUANG H, WENG H, SUN W, et al. Recognition of RNA N(6)- methyladenosine by IGF2BP proteins enhances mRNA stability and translation[J]. Nat Cell Biol, 2018, 20(3): 285-295. DOI: 10.1038/s41556-018-0045-z.
[2]	ZHAO BS, WANG X, BEADELL AV, et al. m(6)A-dependent maternal mRNA clearance facilitates zebrafish maternal-to-zygotic transition[J]. Nature, 2017, 542(7642): 475-478. DOI: 10.1038/nature21355.
[3]	LIU Z, ZHANG J. Human C-to-U coding RNA editing is largely nonadaptive[J]. Mol Biol Evol, 2018, 35(4): 963-969. DOI: 10.1093/molbev/msy011.
[4]	PING XL, SUN BF, WANG L, et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase[J]. Cell Res, 2014, 24(2): 177-189. DOI: 10.1038/cr.2014.3.
[5]	JIA G, FU Y, ZHAO X, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO[J]. Nat Chem Biol, 2011, 7(12): 885-887. DOI: 10.1038/nchembio.687.
[6]	FU Y, JIA G, PANG X, et al. FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA[J]. Nat Commun, 2013, 4: 1798. DOI: 10.1038/ncomms2822.
[7]	SHI H, WANG X, LU Z, et al. YTHDF3 facilitates translation and decay of N(6)-methyladenosine-modified RNA[J]. Cell Res, 2017, 27(3): 315-328. DOI: 10.1038/cr.2017.15.
[8]	HE S, WANG H, LIU R, et al. mRNA N6-methyladenosine methylation of postnatal liver development in pig[J]. PLoS One, 2017, 12(3): e0173421. DOI: 10.1371/journal.pone.0173421.
[9]	NAKANO M, ONDO K, TAKEMOTO S, et al. Methylation of adenosine at the N(6) position post-transcriptionally regulates hepatic P450s expression[J]. Biochem Pharmacol, 2020, 171: 113697. DOI: 10.1016/j.bcp.2019.113697.
[10]	JABS S, BITON A, BÉCAVIN C, et al. Impact of the gut microbiota on the m(6)A epitranscriptome of mouse cecum and liver[J]. Nat Commun, 2020, 11(1): 1344. DOI: 10.1038/s41467-020-15126-x.
[11]	FUSTIN JM, DOIM, YAMAGUCHI Y, et al. RNA-methylation-dependent RNA processing controls the speed of the circadian clock[J]. Cell, 2013, 155(4): 793-806. DOI: 10.1016/j.cell.2013.10.026.
[12]	IMAM H, KHAN M, GOKHALE NS, et al. N6-methyladenosine modification of hepatitis B virus RNA differentially regulates the viral life cycle[J]. Proc Natl Acad Sci U S A, 2018, 115(35): 8829-8834. DOI: 10.1073/pnas.1808319115.
[13]	KIM GW, SIDDIQUI A. Hepatitis B virus X protein recruits methyltransferases to affect cotranscriptional N6-methyladenosine modification of viral/host RNAs[J]. Proc Natl Acad Sci U S A, 2021, 118(3). DOI: 10.1073/pnas.2019455118.
[14]	GOKHALE NS, MCINTYRE A, MCFADDEN MJ, et al. N6-methyladenosine in flaviviridae viral RNA genomes regulates infection[J]. Cell Host Microbe, 2016, 20(5): 654-665. DOI: 10.1016/j.chom.2016.09.015.
[15]	DURBIN AF, WANG C, MARCOTRIGIANO J, et al. RNAs containing modified nucleotides fail to trigger RIG-I conformational changes for innate immune signaling[J]. mBio, 2016, 7(5). DOI: 10.1128/mBio.00833-16.
[16]	GOKHALE NS, MCINTYRE A, MATTOCKS MD, et al. Altered m(6)A modification of specific cellular transcripts affects flaviviridae infection[J]. Mol Cell, 2020, 77(3): 542-555. e8. DOI: 10.1016/j.molcel.2019.11.007.
[17]	RAO X, LAI L, LI X, et al. N(6) -methyladenosine modification of circular RNA circ-ARL3 facilitates hepatitis B virus-associated hepatocellular carcinoma via sponging miR-1305[J]. IUBMB Life, 2021, 73(2): 408-417. DOI: 10.1002/iub.2438.
[18]	KIM GW, SIDDIQUI A. N6-methyladenosine modification of HCV RNA genome regulates cap-independent IRES-mediated translation via YTHDC2 recognition[J]. Proc Natl Acad Sci U S A, 2021, 118(10): e2022024118. DOI: 10.1073/pnas.2022024118.
[19]	KLEINER DE, BRUNT EM, VAN NATTA M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease[J]. Hepatology, 2005, 41(6): 1313-1321. DOI: 10.1002/hep.20701.
[20]	CHEN X, LUO Y, JIA G, et al. FTO promotes adipogenesis through inhibition of the Wnt/β-catenin signaling pathway in porcine intramuscular preadipocytes[J]. Anim Biotechnol, 2017, 28(4): 268-274. DOI: 10.1080/10495398.2016.1273835.
[21]	KANG H, ZHANG Z, YU L, et al. FTO reduces mitochondria and promotes hepatic fat accumulation through RNA demethylation[J]. J Cell Biochem, 2018, 119(7): 5676-5685. DOI: 10.1002/jcb.26746.
[22]	MERKESTEIN M, LABER S, MCMURRAY F, et al. FTO influences adipogenesis by regulating mitotic clonal expansion[J]. Nat Commun, 2015, 6: 6792. DOI: 10.1038/ncomms7792.
[23]	WU R, LIU Y, YAO Y, et al. FTO regulates adipogenesis by controlling cell cycle progression via m(6)A-YTHDF2 dependent mechanism[J]. Biochim Biophys Acta Mol Cell Biol Lipids, 2018, 1863(10): 1323-1330. DOI: 10.1016/j.bbalip.2018.08.008.
[24]	WANG X, ZHU L, CHEN J, et al. mRNA m⁶A methylation downregulates adipogenesis in porcine adipocytes[J]. Biochem Biophys Res Commun, 2015, 459(2): 201-207. DOI: 10.1016/j.bbrc.2015.02.048.
[25]	XIE W, MA LL, XU YQ, et al. METTL3 inhibits hepatic insulin sensitivity via N6-methyladenosine modification of Fasn mRNA and promoting fatty acid metabolism[J]. Biochem Biophys Res Commun, 2019, 518(1): 120-126. DOI: 10.1016/j.bbrc.2019.08.018.
[26]	CHEN J, ZHOU X, WU W, et al. FTO-dependent function of N6- methyladenosine is involved in the hepatoprotective effects of betaine on adolescent mice[J]. J Physiol Biochem, 2015, 71(3): 405-413. DOI: 10.1007/s13105-015-0420-1.
[27]	ZHOU X, CHEN J, CHEN J, et al. The beneficial effects of betaine on dysfunctional adipose tissue and N6-methyladenosine mRNA methylation requires the AMP-activated protein kinase α1 subunit[J]. J Nutr Biochem, 2015, 26(12): 1678-1684. DOI: 10.1016/j.jnutbio.2015.08.014.
[28]	LU N, LI X, YU J, et al. Curcumin attenuates lipopolysaccharide-induced hepatic lipid metabolism disorder by modification of m(6)A RNA methylation in piglets[J]. Lipids, 2018, 53(1): 53-63. DOI: 10.1002/lipd.12023.
[29]	LIU XY, LIU RX, HOU F, et al. Fibronectin expression is critical for liver fibrogenesis in vivo and inïvitro[J]. Mol Med Rep, 2016, 14(4): 3669-3675. DOI: 10.3892/mmr.2016.5673.
[30]	CUI Z, HUANG N, LIU L, et al. Dynamic analysis of m6A methylation spectroscopy during progression and reversal of hepatic fibrosis[J]. Epigenomics, 2020, 12(19): 1707-1723. DOI: 10.2217/epi-2019-0365.
[31]	ZHU Y, PAN X, DU N, et al. ASIC1a regulates miR-350/SPRY2 by N(6) -methyladenosine to promote liver fibrosis[J]. FASEB J, 2020, 34(11): 14371-14388. DOI: 10.1096/fj.202001337R.
[32]	BRAY F, FERLAY J, SOERJOMATARAM I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6): 394-424. DOI: 10.3322/caac.21492.
[33]	CHEN M, WEI L, LAW CT, et al. RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2[J]. Hepatology, 2018, 67(6): 2254-2270. DOI: 10.1002/hep.29683.
[34]	MA JZ, YANG F, ZHOU CC, et al. METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N(6) -methyladenosine-dependent primary MicroRNA processing[J]. Hepatology, 2017, 65(2): 529-543. DOI: 10.1002/hep.28885.
[35]	YANG Z, LI J, FENG G, et al. MicroRNA-145 modulates N(6)-methyladenosine levels by targeting the 3'-untranslated mRNA region of the N(6)-methyladenosine binding YTH domain family 2 protein[J]. J Biol Chem, 2017, 292(9): 3614- 3623. DOI: 10.1074/jbc.M116.749689.
[36]	LI J, ZHU L, SHI Y, et al. m6A demethylase FTO promotes hepatocellular carcinoma tumorigenesis via mediating PKM2 demethylation[J]. Am J Transl Res, 2019, 11(9): 6084-6092.
[37]	CHEN Y, ZHAO Y, CHEN J, et al. ALKBH5 suppresses malignancy of hepatocellular carcinoma via m(6)A-guided epigenetic inhibition of LYPD1[J]. Mol Cancer, 2020, 19(1): 123. DOI: 10.1186/s12943-020-01239-w.
[38]	WU X, ZHANG X, TAO L, et al. Prognostic value of an m6A RNA methylation regulator-based signature in patients with hepatocellular carcinoma[J]. Biomed Res Int, 2020, 2020: 2053902. DOI: 10.1155/2020/2053902.
[39]	LIN Z, NIU Y, WAN A, et al. RNA m(6) A methylation regulates sorafenib resistance in liver cancer through FOXO3-mediated autophagy[J]. EMBO J, 2020, 39(12): e103181. DOI: 10.15252/embj.2019103181.