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Nuclear m6A Reader YTHDC1 suppresses proximal Alternative Polyadenylation sites by Interfering with the 3' Processing Machinery

ABSTRACT: 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.

SUBMITTER: Liutao Chen

PROVIDER: S-SCDT-10_15252-EMBR_202254686 | biostudies-other |

REPOSITORIES: biostudies-other

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

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U1 snRNP proteins promote proximal alternative polyadenylation sites by directly interacting with 3' end processing core factors.

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The m6A reader CPSF30-L regulates alternative polyadenylation affecting nitrate signaling in Arabidopsis

Project description:As the most ubiquitous internal modification of eukaryotic mRNA, m6A (N6-methyladenosine) modification plays a vital role in almost every aspect of mRNA metabolism. However, the evidence of m6A in regulating the alternative polyadenylation (APA) is limited. APA is controlled by a large protein-RNA complex with many components including CPSF30. Arabidopsis CPSF30 has two isoforms, the longer one named CPSF30-L containing an additional YTH (YT512-B Homology)-domain in the C terminus, which is unique in plant. In this study, we revealed that m6A modification directly regulated APA, by proving the capability of Arabidopsis CPSF30-L YTH domain binding to m6A substrate by using in vitro assay and structural studies. We observed that extensive genes shifted their poly(A) sites in cpsf30-2 and found that numerous genes altered polyadenylation site (PAS) that correlated well with previously identified m6A peaks, indicating that genes carry m6A modification are prone to be regulated by APA. Moreover, we found that several important genes involved in nitrate metabolism are amongst those genes with APA site alteration in cpsf30-2.And we could rescue these APA and nitrate metabolism defects by introducing the wild-type CPSF30-L, but not by m6A-binding defective mutants (W259A, W310A or Y319A), which explained the nitrogen signaling defects of cpsf30-2 discovered previously. Taken together, our results demonstrated that m6A modification could directly regulate APA in Arabidopsis and revealed the function of m6A reader CPSF30-L in nitrate signaling by controlling APA regulation. This study will shed new lights on the roles of m6A modification during RNA 3’-end processing in plant development.

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