mRNA的N~6-甲基腺嘌呤研究进展
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摘要
N~6-甲基腺嘌呤(N~6-methyladenosine,m~6A)是真核生物mRNA内最常见的修饰。该修饰过程是动态可逆的,并由甲基转移酶复合体、去甲基化酶和相应的读码器协同调控。近年来,随着m~6A测序技术的发展,m~6A的生物学功能已备受关注,并成为生命科学热门研究领域之一。对动物和植物体中m~6A修饰的分布特征、m~6A甲基化的动态调控、m~6A的识别以及m~6A修饰对mRNA的调控最新研究进展进行了综述,以推进对m~6A甲基化修饰的生物学功能及作用机制研究。
N~6-methyladenosine( m~6A) is the most prevalent internal modification in eukaryotic mRNA.Recent studies have shown that the modification of m~6A is dynamic and reversible,which is modulated by multiprotein methyltransferase complex,demethylase and readers. Recently,m~6A modification has received significant attention as the technology for m~6A identification continuously developed. The modification of m~6A has become one of the hot topics in life science. We summarized the recent progresses on m~6A modification including m~6A distribution patterns at transcriptome-wide and organ level,dynamic regulation,recognition and regulation of mRNA fate. The review will help us better understand the biological importance of m~6A modification and its action mechanism.
N~6-methyladenosine( m~6A) is the most prevalent internal modification in eukaryotic mRNA.Recent studies have shown that the modification of m~6A is dynamic and reversible,which is modulated by multiprotein methyltransferase complex,demethylase and readers. Recently,m~6A modification has received significant attention as the technology for m~6A identification continuously developed. The modification of m~6A has become one of the hot topics in life science. We summarized the recent progresses on m~6A modification including m~6A distribution patterns at transcriptome-wide and organ level,dynamic regulation,recognition and regulation of mRNA fate. The review will help us better understand the biological importance of m~6A modification and its action mechanism.
引文
[1] BOCCALETTO P,MACHNICKA M A,PURTA E,et al. MODOMICS:A database of RNA modification pathways:2017update[J]. Nucleic Acids Res,2018,46(1):D303-D307.
[2] LIU J,JIA G. Methylation modifications in eukaryotic messenger RNA[J]. J Genet Genomics,2014,41(1):21-33.
[3] LUO G Z,MACQUEEN A,ZHENG G,et al. Unique features of the m6A methylome in Arabidopsis thaliana[J].Nat Commun,2014,5:5630.
[4] WAN Y,TANG K,ZHANG D,et al. Transcriptome-wide high-throughput deep m6A-seq reveals unique differential m6A methylation patterns between three organs in Arabidopsis thaliana[J]. Genome Biol,2015,16:272.
[5] LI Y,WANG X,LI C,et al. Transcriptome-wide N6-methyladenosine profiling of rice callus and leaf reveals the presence of tissue-specific competitors involved in selective m RNA modification[J]. RNA Biol,2014,11(9):1180-1188.
[6] SCHWARTZ S,AGARWALA S D,MUMBACH M R,et al. High-resolution mapping reveals a conserved,widespread,dynamic m RNA methylation program in yeast meiosis[J]. Cell,2013,155(6):1409-1421.
[7] DOMINISSINI D,MOSHITCH-MOSHKOVITZ S,SCHWARTZ S. et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq[J]. Nature,2012,485:201-206.
[8] MEYER K D,SALETORE Y,ZUMBO P,et al. Comprehensive analysis of m RNA methylation reveals enrichment in 3'UTRs and near stop eodons[J]. Cell,2012,149(7):1635-1646.
[9] CARROLL S M,NARAYAN P,ROTTMAN F M. N6-methyladenosine residues in an intron-specific region of prolactin premessenger-RNA[J]. Mol Cell Biol,1990,10(9):4456-4465.
[10] BOKAR J A,RATH-SHAMBAUGH M E,LUDWICZAK R,et al. Characterization and partial purification of m RNA N6-adenosine methyltransferase from He La cell nuclei. Internal m RNA methylation requires a multisubunit complex[J]. J Biol Chem,1994,269:17697-17704.
[11] 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.
[12] BUJNICKI J M,FEDER M,RADLINSKA M,et al. Structure prediction and phylogenetic analysis of a functionally diverse family of proteins homologous to the MTA70 subunit of the human tu RNA:moA methyltransferase[J].J Mol Evol,2002,55(4):431-444.
[13] WANG Y,LI Y,TOTH J I,et al. N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells[J]. Nat Cell Biol,2014,16:191-198.
[14] LIU J,YUE Y,HAN D,et al. A METTL3-METTL14complex mediates mammalian nuclear RNA N6-adenosine methylation[J]. Nat Chem Biol,2014,10:93-95.
[15] WARDA A S,KRETSCHMER J,HACKERT P,et al.Human METTL16 is a N6-methyladenosine(m6A)methyltransferase that targets pre-mRNAs and various noncoding RNAs[J]. EMBO Rep,2017,18(11):2004-2014.
[16] SCHWARTZ S,MUMBACH M R,JOVANOVIC M,et al. Perturbation of m6A writers reveals two distinct classes of m RNA methylation at internal and 5'sites[J].Cell Rep,2014,8(1):284-296.
[17] PING X L,SUN B F,WANG L,et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase[J]. Cell Res,2014,24:177-189.
[18] YUE Y,LIU J,CUI X,et al. VIRMA mediates preferential m6A m RNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation[J].Cell Discov,2018,4:10.
[19] PATIL D P,CHEN C K,PICKERING B F,et al. m6A RNA methylation promotes XIST-mediated transcriptional repression[J]. Nature,2016,537:369-373.
[20] HORIUCHI K,KAWAMURA T,IWANARI H,et al.Identification of Wilms’tumor 1-associating protein complex and its role in alternative splicing and the cell cycle[J]. J Biol Chem,2013,288:33292-33302.
[21] BODI Z,ZHONG S,MEHRA S,et al. Adenosine methylation in Arabidopsis m RNA is associated with the 3'end and reduced levels cause developmental defects[J].Front Plant Sci,2012,3(48):1-10.
[22] SCUTENAIRE J,DERAGON J M,JEAN V,et al. The YTH domain protein ECT2 is an m6A reader required for normal trichome branching in Arabidopsis[J]. Plant Cell,2018,30(5):986-1005.
[23] ZHONG S,LI H,BODI Z,et al. MTA is an Arabidopsis messenger RNA adenosine methylase and interacts with a homolog of a sex-specific splicing factor[J]. The Plant cell,2008,20(5):1278-1288.
[24] XU C,LIU K,TEMPEL W,et al. Structures of human ALKBH5 demethylase reveal a unique binding mode for specific single-stranded N-6-methyladenosine RNA demethylation[J]. J Biol Chem,2014,289:17299-17311.
[25] MAUER J,LUO X,BLANJOIE A,et al. Reversible methylation of m6Amin the 5'cap controls m RNA stability[J]. Nature,2017,541:371-375.
[26] ZHENG G,DAHL J A,NIU Y,et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility[J]. Mol Cell,2013,49:18-29.
[27] MARTNEZ-PREZ M,APARICIO F,LPEZ-GRESA M P,et al. Arabidopsis m6A demethylase activity modulates viral infection of a plant virus and the m6A abundance in its genomic RNAs[J]. Proc Natl Acad Sci USA,2017,114:10755-10760.
[28] DUAN H C,WEI L H,ZHANG C,et al. ALKBH10B is an RNA N6-methyladenosine demethylase affecting Arabidopsis floral transition[J]. Plant Cell,2017,29:2995-3011.
[29] WANG X,ZHAO B S,ROUNDTREE I A,et al. N6-methyladenosine modulates messenger RNA translation efficiency[J]. Cell,2015,161:1388-1399.
[30] XIAO W,ADHIKARI S,DAHAL U,et al. Nuclear m6A reader YTHDC1 regulates m RNA splicing[J]. Mol Cell,2016,61:507-519.
[31] THELER D,DOMINGUEZ C,BLATTER M,et al. Solution structure of the YTH domain in complex with N6-methyladenosine RNA:A reader of methylated RNA[J].Nucleic Acids Res,2014,42:13911-13919.
[32] HUANG H,WENG H,SUN W,et al. Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances m RNA stability and translation[J]. Nat Cell Biol,2018,20:285-295.
[33] WEI L H,SONG P,WANG Y,et al. The m6A reader ECT2 Controls trichome morphology by affecting m RNA stability in Arabidopsis[J]. Plant Cell,2018,30(5):968-985.
[34] GEULA S,MOSHITCH-MOSHKOVITZ S,DOMINISSINI D,et al. Stem cells m6A m RNA methylation facilitates resolution of na6ve pluripotency toward differentiation[J]. Science,2015,347:1002-1006.
[35] WANG X,LU Z,GOMEZ A,et al. N6-methyladenosinedependent regulation of messenger RNA stability[J].Nature,2014,505:117-120.
[36] ZHANG C,CHEN Y,SUN B,et al. m6A modulates haematopoietic stem and progenitor cell specification[J]. Nature,2017,549(7671):273-276.
[37] SALDITT-GEORGIEFF M,JELINEK W,DARNELL J E,et al. Methyl labeling of He La cell hn RNA:A comparison with m RNA[J]. Cell,1976,7:227-237.
[38] SLEEMAN J E,TRINKLE-MULCAHY L. Nuclear bodies:New insights into assembly/dynamics and disease relevance[J]. Curr Opin Cell Biol,2014,28:76-83.
[39] LIU N,DAI Q,ZHENG G,et al. N6-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions[J]. Nature,2015,518:560-564.
[40] ZHAO X,YANG Y,SUN B F,et al. FTO-dependent demethylation of N6-methyladenosine regulates m RNA splicing and is required for adipogenesis[J]. Cell Res,2014,24:1403-1419.
[41] ZHOU J,WAN J,GAO X,et al. Dynamic m6A m RNA methylation directs translational control of heat shock response[J]. Nature,2015,526:591-594.
[42] LIN S,CHOE J,DU P,et al. The m6A methyltransferase METTL3 promotes translation in human cancer cells[J]. Mol Cell,2016,62:335-345.
[43] KARIKK,MURAMATSU H,WELSH F A,et al. Incorporation of pseudouridine into m RNA yields superior nonimmunogenic vector with increased translational capacity and biological stability[J]. Mol Ther,2008,16:1833-1840.
[44] CHOI J,IEONG K W,DEMIRCI H,et al. N6-methyladenosine in m RNA disrupts t RNA selection and translation-elongation dynamics[J]. Nat Struct Mol Biol,2016,23:110-115.
[2] LIU J,JIA G. Methylation modifications in eukaryotic messenger RNA[J]. J Genet Genomics,2014,41(1):21-33.
[3] LUO G Z,MACQUEEN A,ZHENG G,et al. Unique features of the m6A methylome in Arabidopsis thaliana[J].Nat Commun,2014,5:5630.
[4] WAN Y,TANG K,ZHANG D,et al. Transcriptome-wide high-throughput deep m6A-seq reveals unique differential m6A methylation patterns between three organs in Arabidopsis thaliana[J]. Genome Biol,2015,16:272.
[5] LI Y,WANG X,LI C,et al. Transcriptome-wide N6-methyladenosine profiling of rice callus and leaf reveals the presence of tissue-specific competitors involved in selective m RNA modification[J]. RNA Biol,2014,11(9):1180-1188.
[6] SCHWARTZ S,AGARWALA S D,MUMBACH M R,et al. High-resolution mapping reveals a conserved,widespread,dynamic m RNA methylation program in yeast meiosis[J]. Cell,2013,155(6):1409-1421.
[7] DOMINISSINI D,MOSHITCH-MOSHKOVITZ S,SCHWARTZ S. et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq[J]. Nature,2012,485:201-206.
[8] MEYER K D,SALETORE Y,ZUMBO P,et al. Comprehensive analysis of m RNA methylation reveals enrichment in 3'UTRs and near stop eodons[J]. Cell,2012,149(7):1635-1646.
[9] CARROLL S M,NARAYAN P,ROTTMAN F M. N6-methyladenosine residues in an intron-specific region of prolactin premessenger-RNA[J]. Mol Cell Biol,1990,10(9):4456-4465.
[10] BOKAR J A,RATH-SHAMBAUGH M E,LUDWICZAK R,et al. Characterization and partial purification of m RNA N6-adenosine methyltransferase from He La cell nuclei. Internal m RNA methylation requires a multisubunit complex[J]. J Biol Chem,1994,269:17697-17704.
[11] 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.
[12] BUJNICKI J M,FEDER M,RADLINSKA M,et al. Structure prediction and phylogenetic analysis of a functionally diverse family of proteins homologous to the MTA70 subunit of the human tu RNA:moA methyltransferase[J].J Mol Evol,2002,55(4):431-444.
[13] WANG Y,LI Y,TOTH J I,et al. N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells[J]. Nat Cell Biol,2014,16:191-198.
[14] LIU J,YUE Y,HAN D,et al. A METTL3-METTL14complex mediates mammalian nuclear RNA N6-adenosine methylation[J]. Nat Chem Biol,2014,10:93-95.
[15] WARDA A S,KRETSCHMER J,HACKERT P,et al.Human METTL16 is a N6-methyladenosine(m6A)methyltransferase that targets pre-mRNAs and various noncoding RNAs[J]. EMBO Rep,2017,18(11):2004-2014.
[16] SCHWARTZ S,MUMBACH M R,JOVANOVIC M,et al. Perturbation of m6A writers reveals two distinct classes of m RNA methylation at internal and 5'sites[J].Cell Rep,2014,8(1):284-296.
[17] PING X L,SUN B F,WANG L,et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase[J]. Cell Res,2014,24:177-189.
[18] YUE Y,LIU J,CUI X,et al. VIRMA mediates preferential m6A m RNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation[J].Cell Discov,2018,4:10.
[19] PATIL D P,CHEN C K,PICKERING B F,et al. m6A RNA methylation promotes XIST-mediated transcriptional repression[J]. Nature,2016,537:369-373.
[20] HORIUCHI K,KAWAMURA T,IWANARI H,et al.Identification of Wilms’tumor 1-associating protein complex and its role in alternative splicing and the cell cycle[J]. J Biol Chem,2013,288:33292-33302.
[21] BODI Z,ZHONG S,MEHRA S,et al. Adenosine methylation in Arabidopsis m RNA is associated with the 3'end and reduced levels cause developmental defects[J].Front Plant Sci,2012,3(48):1-10.
[22] SCUTENAIRE J,DERAGON J M,JEAN V,et al. The YTH domain protein ECT2 is an m6A reader required for normal trichome branching in Arabidopsis[J]. Plant Cell,2018,30(5):986-1005.
[23] ZHONG S,LI H,BODI Z,et al. MTA is an Arabidopsis messenger RNA adenosine methylase and interacts with a homolog of a sex-specific splicing factor[J]. The Plant cell,2008,20(5):1278-1288.
[24] XU C,LIU K,TEMPEL W,et al. Structures of human ALKBH5 demethylase reveal a unique binding mode for specific single-stranded N-6-methyladenosine RNA demethylation[J]. J Biol Chem,2014,289:17299-17311.
[25] MAUER J,LUO X,BLANJOIE A,et al. Reversible methylation of m6Amin the 5'cap controls m RNA stability[J]. Nature,2017,541:371-375.
[26] ZHENG G,DAHL J A,NIU Y,et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility[J]. Mol Cell,2013,49:18-29.
[27] MARTNEZ-PREZ M,APARICIO F,LPEZ-GRESA M P,et al. Arabidopsis m6A demethylase activity modulates viral infection of a plant virus and the m6A abundance in its genomic RNAs[J]. Proc Natl Acad Sci USA,2017,114:10755-10760.
[28] DUAN H C,WEI L H,ZHANG C,et al. ALKBH10B is an RNA N6-methyladenosine demethylase affecting Arabidopsis floral transition[J]. Plant Cell,2017,29:2995-3011.
[29] WANG X,ZHAO B S,ROUNDTREE I A,et al. N6-methyladenosine modulates messenger RNA translation efficiency[J]. Cell,2015,161:1388-1399.
[30] XIAO W,ADHIKARI S,DAHAL U,et al. Nuclear m6A reader YTHDC1 regulates m RNA splicing[J]. Mol Cell,2016,61:507-519.
[31] THELER D,DOMINGUEZ C,BLATTER M,et al. Solution structure of the YTH domain in complex with N6-methyladenosine RNA:A reader of methylated RNA[J].Nucleic Acids Res,2014,42:13911-13919.
[32] HUANG H,WENG H,SUN W,et al. Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances m RNA stability and translation[J]. Nat Cell Biol,2018,20:285-295.
[33] WEI L H,SONG P,WANG Y,et al. The m6A reader ECT2 Controls trichome morphology by affecting m RNA stability in Arabidopsis[J]. Plant Cell,2018,30(5):968-985.
[34] GEULA S,MOSHITCH-MOSHKOVITZ S,DOMINISSINI D,et al. Stem cells m6A m RNA methylation facilitates resolution of na6ve pluripotency toward differentiation[J]. Science,2015,347:1002-1006.
[35] WANG X,LU Z,GOMEZ A,et al. N6-methyladenosinedependent regulation of messenger RNA stability[J].Nature,2014,505:117-120.
[36] ZHANG C,CHEN Y,SUN B,et al. m6A modulates haematopoietic stem and progenitor cell specification[J]. Nature,2017,549(7671):273-276.
[37] SALDITT-GEORGIEFF M,JELINEK W,DARNELL J E,et al. Methyl labeling of He La cell hn RNA:A comparison with m RNA[J]. Cell,1976,7:227-237.
[38] SLEEMAN J E,TRINKLE-MULCAHY L. Nuclear bodies:New insights into assembly/dynamics and disease relevance[J]. Curr Opin Cell Biol,2014,28:76-83.
[39] LIU N,DAI Q,ZHENG G,et al. N6-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions[J]. Nature,2015,518:560-564.
[40] ZHAO X,YANG Y,SUN B F,et al. FTO-dependent demethylation of N6-methyladenosine regulates m RNA splicing and is required for adipogenesis[J]. Cell Res,2014,24:1403-1419.
[41] ZHOU J,WAN J,GAO X,et al. Dynamic m6A m RNA methylation directs translational control of heat shock response[J]. Nature,2015,526:591-594.
[42] LIN S,CHOE J,DU P,et al. The m6A methyltransferase METTL3 promotes translation in human cancer cells[J]. Mol Cell,2016,62:335-345.
[43] KARIKK,MURAMATSU H,WELSH F A,et al. Incorporation of pseudouridine into m RNA yields superior nonimmunogenic vector with increased translational capacity and biological stability[J]. Mol Ther,2008,16:1833-1840.
[44] CHOI J,IEONG K W,DEMIRCI H,et al. N6-methyladenosine in m RNA disrupts t RNA selection and translation-elongation dynamics[J]. Nat Struct Mol Biol,2016,23:110-115.