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 0 UTR transcripts by binding to their upstream m 6 A sites. YTHDC1 can directly interact with the 3 0 end processing factor FIP1L1 and interfere with its ability to recruit CPSF4. Binding to the m 6 A sites can promote liquidliquid 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 0 end processing, providing a new mechanism for APA regulation.
The mechanistic understanding of virus infection and inflammation in many diseases is incomplete. Normally, messenger RNA (mRNA) tails of replication‐dependent histones (RDH) that safeguard naked nuclear DNAs are protected by a specialized stem‐loop instead of polyadenylation. Here, we showed that infection by various RNA viruses (including severe acute respiratory syndrome coronavirus 2) induced aberrant polyadenylation of RDH mRNAs (pARDH) that resulted in inflammation or cellular senescence, based on which we constructed a pARDH inflammation score (pARIS). We further investigated pARIS elevation in various disease conditions, including different types of virus infection, cancer, and cellular senescence. Notably, we found that pARIS was positively correlated with coronavirus disease 2019 severity in specific immune cell types. We also detected a subset of HIV‐1 elite controllers characterized by pARDH “flipping” potentially mediated by HuR. Importantly, pARIS was positively associated with transcription of endogenous retrovirus but negatively associated with most immune cell infiltration in tumors of various cancer types. Finally, we identified and experimentally verified two pARIS regulators, ADAR1 and ZKSCAN1, which was first linked to inflammation. The ZKSCAN1 was known as a transcription factor but instead was shown to regulate pARIS as a novel RNA binding protein. Both regulators were upregulated under most infection and inflammation conditions. In conclusion, we unraveled a potential antiviral mechanism underlying various types of virus infections and cancers.
In eukaryotic cells, both alternative splicing and alternative polyadenylation (APA) play essential roles in gene regulation network. U1 small ribonucleoprotein particle (U1 snRNP) is a major component of spliceosome, and U1 snRNP complex can suppress proximal APA sites through crosstalking with 3′ end processing factors. However, here we show that both knockdown and overexpression of SNRPA, SNRPC, SNRNP70, and SNRPD2, the U1 snRNP proteins, promote the usage of proximal APA sites in transcriptome level. SNRNP70 can drive the phase transition of PABPN1 from droplet to aggregate, which may reduce the repression effects of PABPN1 on the proximal APA sites. Additionally, SNRNP70 can also promote the proximal APA sites by recruiting CPSF6, suggesting that the function of CPSF6 on APA is related with other RNA binding proteins and cell context-dependent. Consequently, these results reveal that, on the contrary to U1 snRNP complex, the free proteins of U1 snRNP complex can promote proximal APA sites through the interaction with 3′ end processing machinery.
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