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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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2022-03-11 | GSE198143 | GEO

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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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Project description: Not available

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Project description:Skeletal muscle stem cells (also known as satellite cells [SCs]) are essential for muscle regeneration and the regenerative activities of SCs are intrinsically governed by gene regulatory mechanisms, but the post-transcriptional regulation in SCs remains largely unknown. N(6)-methyladenosine (m6A) modification of RNAs is the most pervasive and highly conserved RNA modification in eukaryotic cells; it exerts powerful impact on almost all aspects of mRNA processing that is mainly endowed by its binding with m6A reader proteins. In this study, we investigate the previously uncharacterized regulatory roles of YTHDC1, an m6A reader in mouse SCs. Our results demonstrate that YTHDC1 is an essential regulator of SC activation and proliferation upon acute injury-induced muscle regeneration. The induction of YTHDC1 is indispensable for SC activation and proliferation; thus, inducible YTHDC1 depletion almost abolishes SC regenerative capacity. Mechanistically, transcriptome-wide profiling using LACE-seq in both SCs and mouse C2C12 myoblasts identifies m6A-mediated binding targets of YTHDC1. Next, splicing analysis defines splicing mRNA targets of m6A-YTHDC1. Furthermore, nuclear export analysis also leads to the identification of potential mRNA export targets of m6A-YTHDC1 in SCs and C2C12 myoblasts;interestingly, some mRNAs can be regulated at both splicing and export levels. Lastly, we map YTHDC1 interacting protein partners in myoblasts and unveil a myriad of factors governing mRNA splicing, nuclear export, and transcription, among which hnRNPG appears to be a bona fide interacting partner of YTHDC1. Altogether, our findings uncover YTHDC1 as an essential factor controlling SC regenerative ability through multifaceted gene regulatory mechanisms in mouse myoblast cells.

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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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