U1 snRNP telescripting regulates a size–function-stratified human genome

• Published in: Nature structural & molecular biology Vol. 24; no. 11; pp. 993 - 999
• Main Authors: Oh, Jung-Min, Di, Chao, Venters, Christopher C, Guo, Jiannan, Arai, Chie, So, Byung Ran, Pinto, Anna Maria, Zhang, Zhenxi, Wan, Lili, Younis, Ihab, Dreyfuss, Gideon
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2017; Nature Publishing Group
• Subjects: 13; 38; 42; 42/109; 49; 49/91; 631/337/572; 631/80; Biochemistry; Biological Microscopy; Cell survival; Elongation; Gene expression; Gene Expression Regulation; Gene regulation; Genes; Genetic aspects; Genome, Human; Genomes; Humans; Introns; Life Sciences; Membrane Biology; Messenger RNA; Polyadenylation; Protein Structure; Ribonucleic acid; Ribonucleoprotein, U1 Small Nuclear - metabolism; Ribonucleoproteins (small nuclear); RNA; Splicing; Transcription (Genetics); Transcription elongation; Transcription, Genetic
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/nsmb.3473

Genome-wide analyses of the effects of U1 snRNP inhibition in human cells shows that telescripting suppresses premature cleavage and polyadenylation in long introns to sustain expression of large genes important for cell cycle and development. U1 snRNP (U1) functions in splicing introns and telescripting, which suppresses premature cleavage and polyadenylation (PCPA). Using U1 inhibition in human cells, we show that U1 telescripting is selectively required for sustaining long-distance transcription elongation in introns of large genes (median 39 kb). Evidence of widespread PCPA in the same locations in normal tissues reveals that large genes incur natural transcription attrition. Underscoring the importance of U1 telescripting as a gene-size-based mRNA-regulation mechanism, small genes were not sensitive to PCPA, and the spliced-mRNA productivity of ∼1,000 small genes (median 6.8 kb) increased upon U1 inhibition. Notably, these small, upregulated genes were enriched in functions related to acute stimuli and cell-survival response, whereas genes subject to PCPA were enriched in cell-cycle progression and developmental functions. This gene size–function polarization increased in metazoan evolution by enormous intron expansion. We propose that telescripting adds an overarching layer of regulation to size–function-stratified genomes, leveraged by selective intron expansion to rapidly shift gene expression priorities.