Nuclear m 6 A reader YTHDC1 suppresses proximal alternative polyadenylation sites by interfering with the 3′ processing machinery

Abstract

YTHDC1 inhibits proximal poly(A) sites by interfering with FIP1L1 – CPSF4 interaction, which results in mRNA transcripts with longer 3′ UTRs. N6‐methyladenosine (m6A) and alternative polyadenylation (APA) are important regulators of gene expression in eukaryotes. Recently, it was found that m6A is closely related to APA. However, the molecular mechanism of this new APA regulation remains elusive. Here, we show that YTHDC1, a nuclear m6A reader, can suppress proximal APA sites and produce longer 3′ UTR transcripts by binding to their upstream m6A sites. YTHDC1 can directly interact with the 3′ end processing factor FIP1L1 and interfere with its ability to recruit CPSF4. Binding to the m6A 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 m6A "reader" links m6A modification with pre‐mRNA 3′ end processing, providing a new mechanism for APA regulation.