Nuclear m6 A reader YTHDC1 suppresses proximal alternative polyadenylation sites by interfering with the 3' processing machinery

Abstract

N6-methyladenosine (m⁶ A) and alternative polyadenylation (APA) are important regulators of gene expression in eukaryotes. Recently, it was found that m⁶ A is closely related to APA. However, the molecular mechanism of this new APA regulation remains elusive. Here, we show that YTHDC1, a nuclear m⁶ A reader, can suppress proximal APA sites and produce longer 3' UTR transcripts by binding to their upstream m⁶ A sites. YTHDC1 can directly interact with the 3' end processing factor FIP1L1 and interfere with its ability to recruit CPSF4. Binding to the m⁶ 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 m⁶ A "reader" links m⁶ A modification with pre-mRNA 3' end processing, providing a new mechanism for APA regulation.

Keywords: 3′ end processing factor; FIP1L1; YTHDC1; alternative polyadenylation; m6A.