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The SMAD2/3 interactome reveals that TGFβ controls m6A mRNA methylation in pluripotency

2018; Nature Portfolio; Volume: 555; Issue: 7695 Linguagem: Inglês

10.1038/nature25784

1476-4687

Alessandro Bertero, Stephanie Brown, Pedro Madrigal, Anna Osnato, Daniel Ortmann, Loukia Yiangou, Juned Kadiwala, Nina C. Hubner, Igor Ruiz de los Mozos, Christoph Sadée, An‐Sofie Lenaerts, Shota Nakanoh, Rodrigo A. Grandy, Edward Farnell, Jernej Ule, Hendrik G. Stunnenberg, Sasha Mendjan, Ludovic Vallier,

Epigenetics and DNA Methylation

The SMAD2 and SMAD3 protein interactome links TGFβ signalling to diverse effectors including m6A methyltransferase, which has a role in regulating differentiation of human pluripotent stem cells. TGFβ signalling is involved in many different physiological processes, including embryonic development, but there is no complete description of the tasks accomplished by SMAD2/3 proteins, the downstream effectors of TGFβ signals. Ludovic Vallier and colleagues describe the full set of interactions of SMAD2/3 in human pluripotent stem cells. They find that these interactions are linked to diverse molecular processes in addition to transcription. SMAD2/3 also regulates post-transcriptional modification of messenger RNA through regulation of N6-methyladenosine (m6A) deposition onto transcripts that are involved in early fate decisions. This is carried out during differentiation to modulate the stability of the transcript. These findings link extracellular signalling cues to post-transcriptional regulations of fate regulators. The TGFβ pathway has essential roles in embryonic development, organ homeostasis, tissue repair and disease1,2. These diverse effects are mediated through the intracellular effectors SMAD2 and SMAD3 (hereafter SMAD2/3), whose canonical function is to control the activity of target genes by interacting with transcriptional regulators3. Therefore, a complete description of the factors that interact with SMAD2/3 in a given cell type would have broad implications for many areas of cell biology. Here we describe the interactome of SMAD2/3 in human pluripotent stem cells. 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 mediates the conversion of adenosine to N6-methyladenosine (m6A) on RNA4. We show that SMAD2/3 promotes binding of the m6A methyltransferase complex to a subset of transcripts involved in early cell fate decisions. This mechanism destabilizes specific SMAD2/3 transcriptional targets, including the pluripotency factor gene NANOG, priming 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 regulation of the epitranscriptome. These aspects of TGFβ signalling could have far-reaching implications in many other cell types and in diseases such as cancer5.