title: U1 snRNP determines mRNA length and regulates isoform expression.
abstract: U1 snRNP (U1), in addition to its splicing role, protects pre-mRNAs from drastic premature termination by cleavage and polyadenylation (PCPA) at cryptic polyadenylation signals (PASs) in introns. Here, a high-throughput sequencing strategy of differentially expressed transcripts (HIDE-seq) mapped PCPA sites genome wide in divergent organisms. Surprisingly, whereas U1 depletion terminated most nascent gene transcripts within ~1 kb, moderate functional U1 level decreases, insufficient to inhibit splicing, dose-dependently shifted PCPA downstream and elicited mRNA 3' UTR shortening and proximal 3' exon switching characteristic of activated immune and neuronal cells, stem cells, and cancer. Activated neurons' signature mRNA shortening could be recapitulated by U1 decrease and antagonized by U1 overexpression. Importantly, we show that rapid and transient transcriptional upregulation inherent to neuronal activation physiology creates U1 shortage relative to pre-mRNAs. Additional experiments suggest cotranscriptional PCPA counteracted by U1 association with nascent transcripts, a process we term telescripting, ensuring transcriptome integrity and regulating mRNA length.
authors: Howard Hughes Medical Institute, USA.
authors: Michael G
authors: MG
authors: Berg
authors: Larry N
authors: LN
authors: Singh
authors: Ihab
authors: I
authors: Younis
authors: Qiang
authors: Q
authors: Liu
authors: Anna Maria
authors: AM
authors: Pinto
authors: Daisuke
authors: D
authors: Kaida
authors: Zhenxi
authors: Z
authors: Zhang
authors: Sungchan
authors: S
authors: Cho
authors: Scott
authors: S
authors: Sherrill-Mix
authors: Lili
authors: L
authors: Wan
authors: Gideon
authors: G
authors: Dreyfuss
mesh_terms: D000818:Animals; D002460:Cell Line; D004331:Drosophila melanogaster; D055106:Genome-Wide Association Study; D006367:HeLa Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009474:Neurons / Q000378:metabolism; D026721:RNA 3' End Processing; D012322:RNA Precursors / Q000378:metabolism*; D012326:RNA Splicing; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000378:metabolism*
chemical_list: D012322:RNA Precursors; D017412:Ribonucleoprotein, U1 Small Nuclear