Genome organization around nuclear speckles drives mRNA splicing efficiency

• 成果类型: Article
• 署名作者: Bhat, Prashant; Chow, Amy; Emert, Benjamin; Ettlin, Olivia; Quinodoz, Sofia A.; Strehle, Mackenzie; Takei, Yodai; Burr, Alex; Goronzy, Isabel N.; Chen, Allen W.; Huang, Wesley; Ferrer, Jose Lorenzo M.; Soehalim, Elizabeth; Goh, Say-Tar; Chari, Tara; Sullivan, Delaney K.; Blanco, Mario R.; Guttman, Mitchell
• 署名单位: California Institute of Technology; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; Princeton University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4843
• DOI: 10.1038/s41586-024-07429-6
• 发表日期: 2024-05-30
• 关键词: c-terminal domain; polymerase-ii; gene-expression; sr proteins; transcription; sites; localization; compartments; translation; RECRUITMENT

摘要

The nucleus is highly organized, such that factors involved in the transcription and processing of distinct classes of RNA are confined within specific nuclear bodies1,2. One example is the nuclear speckle, which is defined by high concentrations of protein and noncoding RNA regulators of pre-mRNA splicing3. What functional role, if any, speckles might play in the process of mRNA splicing is unclear4,5. Here we show that genes localized near nuclear speckles display higher spliceosome concentrations, increased spliceosome binding to their pre-mRNAs and higher co-transcriptional splicing levels than genes that are located farther from nuclear speckles. Gene organization around nuclear speckles is dynamic between cell types, and changes in speckle proximity lead to differences in splicing efficiency. Finally, directed recruitment of a pre-mRNA to nuclear speckles is sufficient to increase mRNA splicing levels. Together, our results integrate the long-standing observations of nuclear speckles with the biochemistry of mRNA splicing and demonstrate a crucial role for dynamic three-dimensional spatial organization of genomic DNA in driving spliceosome concentrations and controlling the efficiency of mRNA splicing. Nuclear speckles are shown to have a functional role in mRNA splicing, whereby dynamic three-dimensional organization of DNA around these structures mediates splicing efficiency.