The SMAD2/3 interactome reveals that TGFβ controls m(6)A mRNA methylation in pluripotency.
The SMAD2/3 interactome reveals that TGFβ controls m(6)A mRNA methylation in pluripotency.
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DOI：
10.1038/nature25784
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发表时间：
2018-03-08
期刊：
影响因子：
64.8
通讯作者：
Vallier L
中科院分区：
文献类型：
--
作者：
Bertero A;Brown S;Madrigal P;Osnato A;Ortmann D;Yiangou L;Kadiwala J;Hubner NC;de Los Mozos IR;Sadée C;Lenaerts AS;Nakanoh S;Grandy R;Farnell E;Ule J;Stunnenberg HG;Mendjan S;Vallier L
TGFβ通路在胚胎发育、器官稳态、组织修复和疾病中起重要作用。这种多样性的任务是通过细胞内效应SMAD 2/3实现的，其典型功能是通过与转录调节因子相互作用来控制靶基因的活性。然而，在任何给定的细胞类型中与SMAD 2/3相互作用的因子的完整描述仍然缺乏。在这里，我们通过描述SMAD 2/3在人多能干细胞（hPSC）中的相互作用组来解决这个限制。这一分析表明，SMAD 2/3除了在转录中发挥作用外，还参与多个分子过程。特别是，我们确定了与胃L3-胃L14-WTAP复合物的功能性相互作用，其沉积N6-甲基腺苷（m6 A）。我们发现SMAD 2/3促进m6 A甲基转移酶复合物结合到参与早期细胞命运决定的转录子上。这种机制使特定SMAD 2/3转录靶点（包括多能性因子NANOG）不稳定，从而使它们在分化时快速下调，从而能够及时退出多能性。总的来说，这些发现揭示了细胞外信号传导可以通过调节表转录组诱导快速细胞反应的机制。TGFβ信号传导的这些新方面可能在许多其他细胞类型和癌症等疾病中具有深远的影响。
The TGFβ pathway plays an essential role in embryonic development, organ homeostasis, tissue repair, and disease. This diversity of tasks is achieved through the intracellular effector SMAD2/3, whose canonical function is to control activity of target genes by interacting with transcriptional regulators. Nevertheless, a complete description of the factors interacting with SMAD2/3 in any given cell type is still lacking. Here we address this limitation by describing the interactome of SMAD2/3 in human pluripotent stem cells (hPSCs). This analysis reveals that SMAD2/3 is involved in multiple molecular processes in addition to its role in transcription. In particular, we identify a functional interaction with the METTL3-METTL14-WTAP complex, which deposits N6-methyladenosine (m6A). We uncover that SMAD2/3 promotes binding of the m6A methyltransferase complex onto a subset of transcripts involved in early cell fate decisions. This mechanism destabilizes specific SMAD2/3 transcriptional targets, including the pluripotency factor NANOG, thereby poising them for rapid downregulation upon differentiation to enable timely exit from pluripotency. Collectively, these findings reveal the mechanism by which extracellular signalling can induce rapid cellular responses through regulations of the epitranscriptome. These novel aspects of TGFβ signalling could have far-reaching implications in many other cell types and in diseases such as cancer.
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影响因子：
4.4
作者：
Hubner, Nina C.;Nguyen, Luan N.;Stunnenberg, Hendrik G.
通讯作者：
Stunnenberg, Hendrik G.
影响因子：
23.9
作者：
Batista, Pedro J.;Molinie, Benoit;Wang, Jinkai;Qu, Kun;Zhang, Jiajing;Li, Lingjie;Bouley, Donna M.;Lujan, Ernesto;Haddad, Bahareh;Daneshvar, Kaveh;Carter, Ava C.;Flynn, Ryan A.;Zhou, Chan;Lim, Kok-Seong;Dedon, Peter;Wernig, Marius;Mullen, Alan C.;Xing, Yi;Giallourakis, Cosmas C.;Chang, Howard Y.
通讯作者：
Chang, Howard Y.
DOI：
10.1093/bioinformatics/btr020
发表时间：
2011-03-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Down TA;Piipari M;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
影响因子：
12.3
作者：
Conesa A;Madrigal P;Tarazona S;Gomez-Cabrero D;Cervera A;McPherson A;Szcześniak MW;Gaffney DJ;Elo LL;Zhang X;Mortazavi A
通讯作者：
Mortazavi A