Coordination of m(6)A mRNA Methylation and Gene Transcription by ZFP217 Regulates Pluripotency and Reprogramming.
Coordination of m(6)A mRNA Methylation and Gene Transcription by ZFP217 Regulates Pluripotency and Reprogramming.
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DOI：
10.1016/j.stem.2015.09.005
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发表时间：
2015-12-03
期刊：
影响因子：
23.9
通讯作者：
Walsh MJ
中科院分区：
文献类型：
--
作者：
Aguilo F;Zhang F;Sancho A;Fidalgo M;Di Cecilia S;Vashisht A;Lee DF;Chen CH;Rengasamy M;Andino B;Jahouh F;Roman A;Krig SR;Wang R;Zhang W;Wohlschlegel JA;Wang J;Walsh MJ
表观遗传和表观转录网络在维持胚胎干细胞(ESCs)的多能性和体细胞重编程方面具有重要作用。然而，人们对整合这些不同网络的行动的机制只有部分了解。在这里，我们证明了染色质相关的锌指蛋白217(ZFP217)协调表观遗传和表观转录调控。ZFP217与几个表观遗传调控因子相互作用，激活关键多能性基因的转录，并通过隔离酶M6A甲基转移酶样3(METTL3)来调节N6-甲基腺苷(M6A)在其转录产物上的沉积。Zfp217耗尽一贯损害ESC的自我更新和体细胞重编程，在全球范围内增加m6A RNA水平，并增强Nanog、Sox2、Klf4和c-Myc mRNAs的m6A修饰，促进它们的降解。ZFP217结合它自己的靶基因mRNAs，这些mRNAs也是与METTL3相关的，并富含在m6A修饰的转录本的启动子上。总之，这些发现揭示了转录因子如何将基因转录与m6A RNA修饰紧密结合，以确保ESC的身份。
Epigenetic and epitranscriptomic networks have important functions in maintaining pluripotency of embryonic stem cells (ESCs) and somatic cell reprogramming. However the mechanisms integrating the actions of these distinct networks are only partially understood. Here, we show that the chromatin-associated zinc finger protein 217 (ZFP217) coordinates epigenetic and epitranscriptomic regulation. ZFP217 interacts with several epigenetic regulators, activates transcription of key pluripotency genes, and modulates N6-methyladenosine (m6A) deposition on their transcripts by sequestering the enzyme m6A methyltransferase-like 3 (METTL3). Consistently, Zfp217 depletion compromises ESC self-renewal and somatic cell reprogramming, globally increases m6A RNA levels, and enhances m6A modification of Nanog, Sox2, Klf4, and c-Myc mRNAs, promoting their degradation. ZFP217 binds its own target gene mRNAs, which are also METTL3-associated, and is enriched at promoters of m6A-modified transcripts. Collectively, these findings shed light on how a transcription factor can tightly couple gene transcription to m6A RNA modification to insure ESC identity.