Genome organization around nuclear speckles drives mRNA splicing efficiency

Prashant Bhat, Amy Chow, Benjamin Emert, Olivia Ettlin, Sofia A. Quinodoz, Mackenzie Strehle, Yodai Takei, Alex Burr, Isabel N. Goronzy, Allen W. Chen, Wesley Huang, Jose Lorenzo M. Ferrer, Elizabeth Soehalim, Say-Tar Goh, Tara Chari, Delaney K. Sullivan, Mario R. Blanco and Mitchell Guttman ()
Additional contact information
Prashant Bhat: California Institute of Technology
Amy Chow: California Institute of Technology
Benjamin Emert: California Institute of Technology
Olivia Ettlin: California Institute of Technology
Sofia A. Quinodoz: California Institute of Technology
Mackenzie Strehle: California Institute of Technology
Yodai Takei: California Institute of Technology
Alex Burr: California Institute of Technology
Isabel N. Goronzy: California Institute of Technology
Allen W. Chen: California Institute of Technology
Wesley Huang: California Institute of Technology
Jose Lorenzo M. Ferrer: California Institute of Technology
Elizabeth Soehalim: California Institute of Technology
Say-Tar Goh: California Institute of Technology
Tara Chari: California Institute of Technology
Delaney K. Sullivan: California Institute of Technology
Mario R. Blanco: California Institute of Technology
Mitchell Guttman: California Institute of Technology

Nature, 2024, vol. 629, issue 8014, 1165-1173

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41586-024-07429-6

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