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PHF3 regulates neuronal gene expression through the Pol II CTD reader domain SPOC

Author

Listed:
  • Lisa-Marie Appel

    (University of Vienna, Vienna Biocenter (VBC))

  • Vedran Franke

    (Max Delbrück Center)

  • Melania Bruno

    (University of Vienna, Vienna Biocenter (VBC))

  • Irina Grishkovskaya

    (University of Vienna, Vienna Biocenter (VBC))

  • Aiste Kasiliauskaite

    (Masaryk University
    Masaryk University)

  • Tanja Kaufmann

    (University of Vienna, Vienna Biocenter (VBC))

  • Ursula E. Schoeberl

    (Masaryk University)

  • Martin G. Puchinger

    (University of Vienna, Vienna Biocenter (VBC))

  • Sebastian Kostrhon

    (University of Vienna, Vienna Biocenter (VBC))

  • Carmen Ebenwaldner

    (University of Vienna, Vienna Biocenter (VBC))

  • Marek Sebesta

    (Masaryk University)

  • Etienne Beltzung

    (University of Vienna, Vienna Biocenter (VBC))

  • Karl Mechtler

    (Vienna Biocenter (VBC)
    Vienna Biocenter (VBC))

  • Gen Lin

    (Vienna Biocenter (VBC))

  • Anna Vlasova

    (Vienna Biocenter (VBC))

  • Martin Leeb

    (University of Vienna, Vienna Biocenter (VBC))

  • Rushad Pavri

    (Vienna Biocenter (VBC))

  • Alexander Stark

    (Vienna Biocenter (VBC))

  • Altuna Akalin

    (Max Delbrück Center)

  • Richard Stefl

    (Masaryk University
    Masaryk University)

  • Carrie Bernecky

    (Institute of Science and Technology Austria (IST Austria), Am Campus 1)

  • Kristina Djinovic-Carugo

    (University of Vienna, Vienna Biocenter (VBC)
    University of Ljubljana)

  • Dea Slade

    (University of Vienna, Vienna Biocenter (VBC)
    Medical University of Vienna
    Medical University of Vienna)

Abstract

The C-terminal domain (CTD) of the largest subunit of RNA polymerase II (Pol II) is a regulatory hub for transcription and RNA processing. Here, we identify PHD-finger protein 3 (PHF3) as a regulator of transcription and mRNA stability that docks onto Pol II CTD through its SPOC domain. We characterize SPOC as a CTD reader domain that preferentially binds two phosphorylated Serine-2 marks in adjacent CTD repeats. PHF3 drives liquid-liquid phase separation of phosphorylated Pol II, colocalizes with Pol II clusters and tracks with Pol II across the length of genes. PHF3 knock-out or SPOC deletion in human cells results in increased Pol II stalling, reduced elongation rate and an increase in mRNA stability, with marked derepression of neuronal genes. Key neuronal genes are aberrantly expressed in Phf3 knock-out mouse embryonic stem cells, resulting in impaired neuronal differentiation. Our data suggest that PHF3 acts as a prominent effector of neuronal gene regulation by bridging transcription with mRNA decay.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26360-2
    DOI: 10.1038/s41467-021-26360-2
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    Cited by:

    1. 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.
    2. Lisa-Marie Appel & Vedran Franke & Johannes Benedum & Irina Grishkovskaya & Xué Strobl & Anton Polyansky & Gregor Ammann & Sebastian Platzer & Andrea Neudolt & Anna Wunder & Lena Walch & Stefanie Kais, 2023. "The SPOC domain is a phosphoserine binding module that bridges transcription machinery with co- and post-transcriptional regulators," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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