Progress of N6-Methyladenosine Modification in Cardiovascular and Cerebrovascular Diseases

doi:10.3969/j.issn.1673-5765.2021.01.015

Abstract

Abstract:

N6-methyladenosine (m6A) is the most abundant epigenetic modification of RNA. In addition to the characteristics and function of m6A modification and related regulatory proteins m6A methyltransferases, m6A demethylases and m6A binding proteins, this article mainly reviewed the recent research progress and roles of m6A modification in the risk factors of cardiovascular and cerebrovascular diseases such as hypertension and diabetes.

Key words: N6-methyladenosine; Cardiovascular disease; Cerebrovascular disease; Risk factor;Epigenetic modification

摘要：

6-甲基腺苷（N6-methyladenosine，m6A）是丰度最高的RNA表观遗传学修饰。本文介绍m6A修饰及相关调控蛋白m6A甲基转移酶、m6A去甲基化酶及m6A结合蛋白的特点及功能，并重点综述m6A修饰在高血压、糖尿病等心脑血管疾病危险因素中的作用及其在相应疾病发生发展中的最新研究进展。

关键词: N6-甲基腺苷; 心血管疾病; 脑血管疾病; 危险因素; 表观遗传学修饰

YE Wei-Zhen,LIU Xiang-Rong. Progress of N6-Methyladenosine Modification in Cardiovascular and Cerebrovascular Diseases[J]. Chinese Journal of Stroke, 2021, 16(01): 81-86.

叶维贞，刘向荣. N6-甲基腺苷修饰在心脑血管疾病中的研究进展[J]. 中国卒中杂志, 2021, 16(01): 81-86.

References

[1] 《中国脑卒中防治报告2019》编写组. 《中国脑卒中

防治报告2019》概要[J]. 中国脑血管病杂志，2020，

17（5）：272-281.

[2] YAO W, HAN X, GE M, et al. N6-methyladenosine

（m6A）methylation in ischemia-reperfusion injury[J].

Cell Death Dis，2020，11（6）：478.

[3] LI Y，WANG J W，HUANG C Y，et al. RNA N6-

methyladenosine：a promising molecular target in

metabolic diseases[J/OL]. Cell Biosci，2020，10：

19[2020-09-01]. https：//doi.org/10.1186/s13578-020-

00385-4.

[4] DESROSIERS R，FRIDERICI K，ROTTMAN F.

Identification of methylated nucleosides in messenger

RNA from Novikoff hepatoma cells[J]. Proc Natl

Acad Sci USA，1974，71（10）：3971-3975.

[5] ZHANG H，SHI X R，HUANG T，et al. Dynamic

landscape and evolution of m6A methylation in

human[J]. Nucleic Acids Res，2020，48（11）：6251-

6264.

[6] SHI H L，WEI J B，HE C. Where，when，and how：

context-dependent functions of RNA methylation

writers，readers，and erasers[J]. Mol Cell，2019，74

（4）：640-650.

[7] HE L，LI H Y，WU A Q，et al. Functions of N6-

methyladenosine and its role in cancer[J]. Mol

Cancer，2019，18（1）：176.

[8] XIAO S，CAO S，HUANG Q T，et al. The RNA N6-

methyladenosine modification landscape of human

fetal tissues[J]. Nat Cell Biol，2019，21（5）：651-661.

[9] YANG D D，QIAO J，WANG G Y，et al. N6-

Methyladenosine modification of lincRNA 1281

is critically required for mESC differentiation

potential[J]. Nucleic Acids Res，2018，46（8）：3906-

3920.

[10] YANG Y，FAN X J，MAO M W，et al. Extensive

translation of circular RNAs driven by N6-

methyladenosine[J]. Cell Res，2017，27（5）：626-

641.

[11] CHEN Y G，CHEN R，AHMAD S，et al. N6-

methyladenosine modification controls circular RNA

immunity[J]. Mol Cell，2019，76（1）：96-109.

[12] ERSON-BENSAN A E，BEGIK O. m6A modification

and implications for microRNAs[J]. Microrna，2017，

6（2）：97-101.

[13] DUAN H C，WANG Y，JIA G F. Dynamic and

reversible RNA N6-methyladenosine methylation[J/

OL]. Wiley Interdiscip Rev RNA，2019，10（1）：

e1507[2020-09-01]. https：//doi.org/10.1002/

wrna.1507.

[14] WU R F，JIANG D H，WANG Y Z，et al. N6-

methyladenosine（m6A）methylation in mRNA with

a dynamic and reversible epigenetic modification[J].

Mol Biotechnol，2016，58（7）：450-459.

[15] PATIL D P，CHEN C K，PICKERING B F，et al.

m6A RNA methylation promotes XIST-mediated

transcriptional repression[J]. Nature，2016，537

（7620）：369-373.

[16] LEONETTI A M，CHU M Y，RAMNARAIGN F O，

et al. An emerging role of m6A in memory：a case for

translational priming[J]. Int J Mol Sci，2020，21（20）：

7447.

[17] ZACCARA S，JAFFREY S R. A unified model for

the function of YTHDF proteins in regulating m6Amodified

mRNA[J]. Cell，2020，181（7）：1582-1595.

[18] DAI N. The diverse functions of IMP2/IGF2BP2 in

metabolism[J]. Trends Endocrinol Metab，2020，31

（9）：670-679.

[19] GOMES-DUARTE A，LACERDA R，MENEZES J，

et al. eIF3：a factor for human health and disease[J].

RNA Biol，2018，15（1）：26-34.

[20] ZHENG N，SU J，HU H C，et al. Research progress

of N6-methyladenosine in the cardiovascular

system[J/OL]. Med Sci Monit，2020，26：

e921742[2020-09-01]. https：//doi.org/10.12659/

MSM.921742.

[21] MO X B，LEI S F，ZHANG Y H，et al. Examination

of the associations between m6A-associated singlenucleotide

polymorphisms and blood pressure[J].

Hypertens Res，2019，42（10）：1582-1589.

[22] SOUNESS J E，STOUFFER J E，DE SANCHEZ V

C. Effect of N6-methyladenosine on fat-cell glucose

metabolism. Evidence for two modes of action[J].

Biochem Pharmacol，1982，31（24）：3961-3971.

[23] SHEN F，HUANG W，HUANG J T，et al. Decreased

N6-methyladenosine in peripheral blood RNA from

diabetic patients is associated with FTO expression

rather than ALKBH5[J/OL]. J Clin Endocrinol Metab，

2015，100（1）：E148-154[2020-09-01]. https：//doi.

org/10.1210/jc.2014-1893.

[24] YANG Y，SHEN F，HUANG W，et al. Glucose

is involved in the dynamic regulation of m6A in

patients with type 2 diabetes[J]. J Clin Endocrinol

Metab，2019，104（3）：665-673.

[25] ZHOU B，LIU C Z，XU L Y，et al. N6-

methyladenosine reader protein YTHDC2 suppresses liver steatosis via regulation of mRNA stability of

lipogenic genes[J/OL]. Hepatology，2020[2020-09-

01]. https：//doi.org/10.1002/hep.31220.

[26] ZHONG X，YU J Y，FRAZIER K，et al. Circadian

clock regulation of hepatic lipid metabolism by

modulation of m6A mRNA methylation[J]. Cell Rep，

2018，25（7）：1816-1828.

[27] XIE W，MA L L，XU Y Q，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.

[28] MO X B，LEI S F，ZHANG Y H，et al. Genomewide

enrichment of m6A-associated singlenucleotide

polymorphisms in the lipid loci[J].

Pharmacogenomics J，2019，19（4）：347-357.

[29] WANG X X，WU R F，LIU Y H，et al. m6A mRNA

methylation controls autophagy and adipogenesis by

targeting Atg5 and Atg7[J]. Autophagy，2020，16（7）：

1221-1235.

[30] CHEN X L，LUO Y L，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.

[31] MERKESTEIN M，LABER S，MCMURRAY F，

et al. FTO influences adipogenesis by regulating

mitotic clonal expansion[J/OL]. Nat Commun，2015，

6：6792[2020-09-01]. https：//doi.org/10.1038/

ncomms7792.

[32] KOBAYASHI M，OHSUGI M，SASAKO T，et

al. The RNA methyltransferase complex of WTAP，

METTL3，and METTL14 regulates mitotic clonal

expansion in adipogenesis[J/OL]. Mol Cell Biol，

2018，38（16）：e116-118[2020-09-01]. https：//doi.

org/10.1128/MCB.00116-18.

[33] SONG H W，FENG X，ZHANG H，et al. METTL3

and ALKBH5 oppositely regulate m6A modification

of TFEB mRNA，which dictates the fate of hypoxia/

reoxygenation-treated cardiomyocytes[J]. Autophagy，

2019，15（8）：1419-1437.

[34] CHOKKALLA A K，MEHTA S L，KIM T，et al.

Transient focal ischemia significantly alters the m6A

epitranscriptomic tagging of RNAs in the brain[J].

Stroke，2019，50（10）：2912-2921.

[35] GERKEN T，GIRARD C A，TUNG Y C，et

al. The obesity-associated FTO gene encodes

a 2-oxoglutarate-dependent nucleic acid

demethylase[J]. Science，2007，318（5855）：1469-

1472.

[36] MATHIYALAGAN P，ADAMIAK M，

MAYOURIAN J，et al. FTO-dependent N6-

methyladenosine regulates cardiac function during

remodeling and repair[J/OL]. Circulation，2019，

139：518-532[2020-09-01]. https：//doi.org/10.1161/

CIRCULATIONAHA.118.033794.

[37] XU K W，MO Y C，LI D，et al. N6-methyladenosine

demethylases Alkbh5/Fto regulate cerebral ischemiareperfusion

injury[J/OL]. Ther Adv Chronic Dis，

2020，11：2040622320916024[2020-09-01].

https：//doi.org/10.1177/2040622320916024.

[38] LIU X，ZHANG Z B，RUAN J B，et al.

Inflammasome-activated gasdermin D causes

pyroptosis by forming membrane pores[J]. Nature，

2016，535（7610）：153-158.

[39] DIAO M Y，ZHU Y，YANG J，et al. Hypothermia

protects neurons against ischemia/reperfusioninduced

pyroptosis via m6A-mediated activation

of PTEN and the PI3K/Akt/GSK-3β signaling

pathway[J/OL]. Brain Res Bull，2020，159：25-

31[2020-09-01]. https：//doi.org/10.1016/

j.brainresbull.2020.03.011.

[40] ZHENG L B，TANG X L，LU M Y，et al.

microRNA-421-3p prevents inflammatory response

in cerebral ischemia/reperfusion injury through

targeting m6A reader YTHDF1 to inhibit p65 mRNA

translation[J/OL]. Int Immunopharmacol，2020，

88：106937[2020-09-01]. https：//doi.org/10.1016/

j.intimp.2020.106937.