The SMAD2/3 interactome reveals that TGFβ controls m 6 A mRNA methylation in pluripotency

Nature. 2018 Mar 8;555(7695):256-259. doi: 10.1038/nature25784. Epub 2018 Feb 28.

Abstract

The TGFβ pathway has essential roles in embryonic development, organ homeostasis, tissue repair and disease. 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 regulators. 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 RNA. 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 cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins / metabolism
  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Animals
  • Cell Cycle Proteins
  • Cell Differentiation / genetics*
  • Epigenesis, Genetic
  • Humans
  • Methylation
  • Methyltransferases / chemistry
  • Methyltransferases / metabolism
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / metabolism
  • Nanog Homeobox Protein / metabolism
  • Nodal Protein / metabolism
  • Nuclear Proteins / metabolism
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / metabolism*
  • Protein Binding
  • RNA Splicing Factors
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • Signal Transduction
  • Smad2 Protein / metabolism*
  • Smad3 Protein / metabolism*
  • Transcriptome
  • Transforming Growth Factor beta / metabolism*

Substances

  • Cell Cycle Proteins
  • Multiprotein Complexes
  • Nanog Homeobox Protein
  • Nodal Protein
  • Nuclear Proteins
  • RNA Splicing Factors
  • RNA, Messenger
  • SMAD2 protein, human
  • SMAD3 protein, human
  • Smad2 Protein
  • Smad3 Protein
  • Transforming Growth Factor beta
  • WTAP protein, human
  • Activins
  • N6-methyladenosine (m6A)
  • 6-methyladenine mRNA methyltransferase
  • METTL14 protein, human
  • Methyltransferases
  • METTL3 protein, human
  • Adenosine