The crosstalk between RNA mA epitranscriptome and TGFβ signaling pathway contributes to the arrest of cell cycle.

TGFβ signaling pathway is critical for the cell division, differentiation and apoptosis, the aberrant regulation of which will result in severe diseases including cancer. N6-methyl-adenosine (mA) is one of the most abundant modifications on mRNA, it is unclear yet how mA epitranscriptome response to stimulation of TGFβ. Here, we found that cellular mA level of RNA was elevated after TGFβ treatment, which might be regulated by upregulation of WTAP and METTL3. MeRIP-Seq of mRNAs of MCF7 with or without treated by TGFβ showed that mRNA with upregulated mA modification level after TGFβ treatment were enriched in TGFβ signaling pathway. Phosphorylated level of SMAD2 or SMAD3 induced by TGFβ was impaired when WTAP was silenced. Moreover, the mA modification and mRNA level of JunB, which is known as a cell cycle inhibitor, both were increased after induction of TGFβ and decreased after knockdown of WTAP. Intriguingly, growth inhibition caused by TGFβ was rescued in WTAP-knockdown cells. Collectively, these results reveal the key role that mA pathway playing in the cell cycle arrest induced by TGFβ signaling, providing new mechanisms explanation for growth inhibition mediated by TGFβ.