Nuclear m6A reader YTHDC1 suppresses proximal alternative polyadenylation sites by interfering with the 3′ processing machinery

N6-methyladenosine (m(6)A) and alternative polyadenylation (APA) are important regulators of gene expression in eukaryotes. Recently, it was found that m(6)A is closely related to APA. However, the molecular mechanism of this new APA regulation remains elusive. Here, we show that YTHDC1, a nuclear m(6)A reader, can suppress proximal APA sites and produce longer 3' UTR transcripts by binding to their upstream m(6)A sites. YTHDC1 can directly interact with the 3' end processing factor FIP1L1 and interfere with its ability to recruit CPSF4. Binding to the m(6)A sites can promote liquid- liquid phase separation of YTHDC1 and FIP1L1, which may play an important role in their interaction and APA regulation. Collectively, YTHDC1 as an m(6)A reader links m(6)A modification with pre-mRNA 3' end processing, providing a new mechanism for APA regulation.

Automated summary

The N6-methyladenosine (m(6)A) modification and alternative polyadenylation (APA) are important regulators of gene expression. YTHDC1, an m(6)A reader, was found to suppress proximal APA sites and produce longer 3' UTR transcripts by binding to upstream m(6)A sites. The interaction between YTHDC1 and FIP1L1, as well as the liquid-liquid phase separation promoted by m(6)A binding, may play a crucial role in APA regulation.