Pol II phosphorylation regulates a switch between transcriptional and splicing condensates

Yang Eric Guo, John C. Manteiga, Jonathan E. Henninger, Benjamin R. Sabari, Alessandra Dall’Agnese, Nancy M. Hannett, Jan-Hendrik Spille, Lena K. Afeyan, Alicia V. Zamudio, Krishna Shrinivas, Brian J. Abraham, Ann Boija, Tim-Michael Decker, Jenna K. Rimel, Charli B. Fant, Tong Ihn Lee, Ibrahim I. Cisse, Phillip A. Sharp, Dylan J. Taatjes and Richard A. Young ()
Additional contact information
Yang Eric Guo: Whitehead Institute for Biomedical Research
John C. Manteiga: Whitehead Institute for Biomedical Research
Jonathan E. Henninger: Whitehead Institute for Biomedical Research
Benjamin R. Sabari: Whitehead Institute for Biomedical Research
Alessandra Dall’Agnese: Whitehead Institute for Biomedical Research
Nancy M. Hannett: Whitehead Institute for Biomedical Research
Jan-Hendrik Spille: Massachusetts Institute of Technology
Lena K. Afeyan: Whitehead Institute for Biomedical Research
Alicia V. Zamudio: Whitehead Institute for Biomedical Research
Krishna Shrinivas: Massachusetts Institute of Technology
Brian J. Abraham: Whitehead Institute for Biomedical Research
Ann Boija: Whitehead Institute for Biomedical Research
Tim-Michael Decker: University of Colorado
Jenna K. Rimel: University of Colorado
Charli B. Fant: University of Colorado
Tong Ihn Lee: Whitehead Institute for Biomedical Research
Ibrahim I. Cisse: Massachusetts Institute of Technology
Phillip A. Sharp: Massachusetts Institute of Technology
Dylan J. Taatjes: University of Colorado
Richard A. Young: Whitehead Institute for Biomedical Research

Nature, 2019, vol. 572, issue 7770, 543-548

Abstract: Abstract The synthesis of pre-mRNA by RNA polymerase II (Pol II) involves the formation of a transcription initiation complex, and a transition to an elongation complex1–4. The large subunit of Pol II contains an intrinsically disordered C-terminal domain that is phosphorylated by cyclin-dependent kinases during the transition from initiation to elongation, thus influencing the interaction of the C-terminal domain with different components of the initiation or the RNA-splicing apparatus5,6. Recent observations suggest that this model provides only a partial picture of the effects of phosphorylation of the C-terminal domain7–12. Both the transcription-initiation machinery and the splicing machinery can form phase-separated condensates that contain large numbers of component molecules: hundreds of molecules of Pol II and mediator are concentrated in condensates at super-enhancers7,8, and large numbers of splicing factors are concentrated in nuclear speckles, some of which occur at highly active transcription sites9–12. Here we investigate whether the phosphorylation of the Pol II C-terminal domain regulates the incorporation of Pol II into phase-separated condensates that are associated with transcription initiation and splicing. We find that the hypophosphorylated C-terminal domain of Pol II is incorporated into mediator condensates and that phosphorylation by regulatory cyclin-dependent kinases reduces this incorporation. We also find that the hyperphosphorylated C-terminal domain is preferentially incorporated into condensates that are formed by splicing factors. These results suggest that phosphorylation of the Pol II C-terminal domain drives an exchange from condensates that are involved in transcription initiation to those that are involved in RNA processing, and implicates phosphorylation as a mechanism that regulates condensate preference.

Date: 2019
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DOI: 10.1038/s41586-019-1464-0

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