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Pol II phosphorylation regulates a switch between transcriptional and splicing condensates

Author

Listed:
  • Yang Eric Guo

    (Whitehead Institute for Biomedical Research)

  • John C. Manteiga

    (Whitehead Institute for Biomedical Research
    Massachusetts Institute of Technology)

  • 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
    University of Illinois at Chicago)

  • Lena K. Afeyan

    (Whitehead Institute for Biomedical Research
    Massachusetts Institute of Technology)

  • Alicia V. Zamudio

    (Whitehead Institute for Biomedical Research
    Massachusetts Institute of Technology)

  • Krishna Shrinivas

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Brian J. Abraham

    (Whitehead Institute for Biomedical Research
    St Jude Children’s Research Hospital)

  • 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
    Massachusetts Institute of Technology)

  • Dylan J. Taatjes

    (University of Colorado)

  • Richard A. Young

    (Whitehead Institute for Biomedical Research
    Massachusetts Institute of Technology)

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.

Suggested Citation

  • 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 , 2019. "Pol II phosphorylation regulates a switch between transcriptional and splicing condensates," Nature, Nature, vol. 572(7770), pages 543-548, August.
  • Handle: RePEc:nat:nature:v:572:y:2019:i:7770:d:10.1038_s41586-019-1464-0
    DOI: 10.1038/s41586-019-1464-0
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    Cited by:

    1. Hiroaki Ohishi & Seiru Shimada & Satoshi Uchino & Jieru Li & Yuko Sato & Manabu Shintani & Hitoshi Owada & Yasuyuki Ohkawa & Alexandros Pertsinidis & Takashi Yamamoto & Hiroshi Kimura & Hiroshi Ochiai, 2022. "STREAMING-tag system reveals spatiotemporal relationships between transcriptional regulatory factors and transcriptional activity," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Sarah M. Lloyd & Daniel B. Leon & Mari O. Brady & Deborah Rodriguez & Madison P. McReynolds & Junghun Kweon & Amy E. Neely & Laura A. Blumensaadt & Patric J. Ho & Xiaomin Bao, 2022. "CDK9 activity switch associated with AFF1 and HEXIM1 controls differentiation initiation from epidermal progenitors," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. Baolei Yuan & Xuan Zhou & Keiichiro Suzuki & Gerardo Ramos-Mandujano & Mengge Wang & Muhammad Tehseen & Lorena V. Cortés-Medina & James J. Moresco & Sarah Dunn & Reyna Hernandez-Benitez & Tomoaki Hish, 2022. "Wiskott-Aldrich syndrome protein forms nuclear condensates and regulates alternative splicing," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    4. Halima H. Schede & Pradeep Natarajan & Arup K. Chakraborty & Krishna Shrinivas, 2023. "A model for organization and regulation of nuclear condensates by gene activity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    5. Johannes Benedum & Vedran Franke & Lisa-Marie Appel & Lena Walch & Melania Bruno & Rebecca Schneeweiss & Juliane Gruber & Helena Oberndorfer & Emma Frank & Xué Strobl & Anton Polyansky & Bojan Zagrovi, 2023. "The SPOC proteins DIDO3 and PHF3 co-regulate gene expression and neuronal differentiation," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    6. Zhaowei Yu & Qi Wang & Qichen Zhang & Yawen Tian & Guo Yan & Jidong Zhu & Guangya Zhu & Yong Zhang, 2024. "Decoding the genomic landscape of chromatin-associated biomolecular condensates," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    7. Min Lee & Hyungseok C. Moon & Hyeonjeong Jeong & Dong Wook Kim & Hye Yoon Park & Yongdae Shin, 2024. "Optogenetic control of mRNA condensation reveals an intimate link between condensate material properties and functions," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    8. Marta Vicioso-Mantis & Raquel Fueyo & Claudia Navarro & Sara Cruz-Molina & Wilfred F. J. Ijcken & Elena Rebollo & Álvaro Rada-Iglesias & Marian A. Martínez-Balbás, 2022. "JMJD3 intrinsically disordered region links the 3D-genome structure to TGFβ-dependent transcription activation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    9. Weiliang Mo & Junchuan Zhang & Li Zhang & Zhenming Yang & Liang Yang & Nan Yao & Yong Xiao & Tianhong Li & Yaxing Li & Guangmei Zhang & Mingdi Bian & Xinglin Du & Zecheng Zuo, 2022. "Arabidopsis cryptochrome 2 forms photobodies with TCP22 under blue light and regulates the circadian clock," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    10. Akiko Doi & Gianmarco D. Suarez & Rita Droste & H. Robert Horvitz, 2023. "A DEAD-box helicase drives the partitioning of a pro-differentiation NAB protein into nuclear foci," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    11. Shuang Hou & Jiaojiao Hu & Zhaowei Yu & Dan Li & Cong Liu & Yong Zhang, 2024. "Machine learning predictor PSPire screens for phase-separating proteins lacking intrinsically disordered regions," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    12. Katerina Linhartova & Francesco Luca Falginella & Martin Matl & Marek Sebesta & Robert Vácha & Richard Stefl, 2024. "Sequence and structural determinants of RNAPII CTD phase-separation and phosphorylation by CDK7," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    13. Hossein Salari & Geneviève Fourel & Daniel Jost, 2024. "Transcription regulates the spatio-temporal dynamics of genes through micro-compartmentalization," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    14. Ziad Ibrahim & Tao Wang & Olivier Destaing & Nicola Salvi & Naghmeh Hoghoughi & Clovis Chabert & Alexandra Rusu & Jinjun Gao & Leonardo Feletto & Nicolas Reynoird & Thomas Schalch & Yingming Zhao & Ma, 2022. "Structural insights into p300 regulation and acetylation-dependent genome organisation," Nature Communications, Nature, vol. 13(1), pages 1-23, December.
    15. Hui Wang & Boyuan Li & Linyu Zuo & Bo Wang & Yan Yan & Kai Tian & Rong Zhou & Chenlu Wang & Xizi Chen & Yongpeng Jiang & Haonan Zheng & Fangfei Qin & Bin Zhang & Yang Yu & Chao-Pei Liu & Yanhui Xu & J, 2022. "The transcriptional coactivator RUVBL2 regulates Pol II clustering with diverse transcription factors," Nature Communications, Nature, vol. 13(1), pages 1-26, December.
    16. Lisa-Marie Appel & Vedran Franke & Melania Bruno & Irina Grishkovskaya & Aiste Kasiliauskaite & Tanja Kaufmann & Ursula E. Schoeberl & Martin G. Puchinger & Sebastian Kostrhon & Carmen Ebenwaldner & M, 2021. "PHF3 regulates neuronal gene expression through the Pol II CTD reader domain SPOC," Nature Communications, Nature, vol. 12(1), pages 1-24, December.
    17. Mina Farag & Wade M. Borcherds & Anne Bremer & Tanja Mittag & Rohit V. Pappu, 2023. "Phase separation of protein mixtures is driven by the interplay of homotypic and heterotypic interactions," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    18. David Flores-Solis & Irina P. Lushpinskaia & Anton A. Polyansky & Arya Changiarath & Marc Boehning & Milana Mirkovic & James Walshe & Lisa M. Pietrek & Patrick Cramer & Lukas S. Stelzl & Bojan Zagrovi, 2023. "Driving forces behind phase separation of the carboxy-terminal domain of RNA polymerase II," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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