Abstract
N6-methyladenosine (m6A), the most abundant modification in messenger RNAs (mRNAs), is deposited by methyltransferases (“writers”) Mettl3 and Mettl14 and erased by demethylases (“erasers”) Fto and Alkbh5. m6A can be recognized by m6A-binding proteins (“readers”), such as Yth domain family proteins (Ythdfs) and Yth domain-containing protein 1 (Ythdc1). Previous studies have indicated that m6A plays an essential function in various fundamental biological processes, including neurogenesis and neuronal development. Dysregulated m6A modification contributes to neurological disorders, including neurodegenerative diseases. In this review, we summarize the current knowledge about the roles of m6A machinery, including writers, erasers, and readers, in regulating gene expression and the function of m6A in neurodevelopment and neurodegeneration. We also discuss the perspectives for studying m6A methylation.
Highlights
Epigenetics refers to the heritable changes in gene expression and cell state caused by some specific mechanisms, aside from the occurrence of potential genetic sequences
M6A modification is precisely catalyzed by a multi-subunit methyltransferase enzyme complex containing Methyltransferase-like 3 (Mettl3), methyltransferase-like 14 (Mettl14), and other accessory components such as Wilms tumor 1-associated protein (Wtap), a mammalian splicing factor [3]
Emra6sAersregulates gene expression through regulating RNA metabolism and via mTohdeulfatinmgamssRaNnAd soebnecsoitdyi-nagsshoicsitaotneedm(Fotdoi)figeersnaenwdatsraonrsicgriinpatliloynrfeafcetrorresd[2t5o].aIsnamn ooubseeseiNtyS-Cris,ktgraensecarinpdtsisfothr ehfisirtsotniedeancetitfyieltdramn6sAferdaesmesetChByPla(sCe R[2E6B]. bTihnedlionsgs-porfo-ftueinnc)tiaonndmpu3t0a0tairoenmo6fAth-me Fotdoigfiende[1ca6]u.sIendagdrdoiwtiothn,retrtaanrdscartiipotns afonrdhsiesvtoenre nmeeutrhoydltervaenlsofpermaseenEtazlhd2isaorredaelrsso, imnc6lAu-dminogdimfieicdr,oacnedphMaleytt,l3fuknncoticokndaolwbnrariendduecfeesctths,ealnevdeldoeflaEyzehd2pasnydchcoomnsoetqoureanctthivisittyonine hHu3mtrainmse[t2h7y–l2a9t]i.oFntoa-tdleyfsicinieent27m(icHe3sKh2o7wmeed3i)nicnreaaNseSdCpso[s1t2n]a. taElcmtoopritcalEitzyh, 2sigconuiflidcarnetslcouses Mettl3-knockdown-induced deficits in adult neural stem cells (aNSCs) [12]. These findings suggest a crosstalk between RNA modification and transcriptional regulation and reveal a new layer of the mechanism regulating neurogenesis (Figure 2C)
Summary
Epigenetics refers to the heritable changes in gene expression and cell state caused by some specific mechanisms, aside from the occurrence of potential genetic sequences. M6A is installed by methyltransferases (writers), removed by demethylases (erasers), and recognized by m6A binding proteins (readers). M6A modification is precisely catalyzed by a multi-subunit methyltransferase enzyme complex containing Mettl, Mettl, and other accessory components such as Wilms tumor 1-associated protein (Wtap), a mammalian splicing factor [3]. Wtap does not possess any methylation activity but interacts with Mettl and Mettl and promotes the recruitment of the Mettl3–Mettl complex to target transcripts [5]. The presence of m6A modification induces the preferential binding of certain proteins, i.e., m6A readers, pecially enriched at the 5′ and 3′ UTRs [6,7]. M6A has been shown to impact RNA metabolism, including mRNA stability, translation, splicing, and localization; m6A regulates gene expression and involves diverse biological processes [2,8]. TdhyesrdeeglueltaiotinonofoMf met6tlA14hians ebmeebnryfoounnicdnineuarasletstoefmnecuerlloslo(egNicSaCl ds)isloedrtdoearsr,esmuacrhkaasblAe ldzehceriemaseer ’isn dpirsoelaifseer,aFtiroangialnedXimsymndatruorme ed,iafftetreennttioianti-odnefiincivt/ithroyapnedraicntivviivtyo [d1i6s]o. rIdneard(dAitDioHn,DM),eattnl3dkinnotecklldeoctwunalreddisuacbeidlithye[1p9ro,2l1if–e2ra4t]i.onInanthdisskrewvieedwt,hwe edisffuemremntai-aritzioenthoef aredcuelnt tnfeiunrdailnsgtsemregcealrlds i(nagNtShCes)futonwctaiordnsannedurboinolaolglincaelagceo,nwsehqiuleenthceesnoewf mbo6rAn modification in the neural system, from neural development to brain function and neurological disorders
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