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The SPOC proteins DIDO3 and PHF3 co-regulate gene expression and neuronal differentiation

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  • Johannes Benedum

    (Medical University of Vienna, Max Perutz Labs, Vienna Biocenter
    Medical University of Vienna
    Medical University of Vienna
    a Doctoral School of the University of Vienna and Medical University of Vienna)

  • Vedran Franke

    (The Berlin Institute for Medical Systems Biology, Max Delbrück Center)

  • Lisa-Marie Appel

    (Medical University of Vienna, Max Perutz Labs, Vienna Biocenter
    Medical University of Vienna
    Medical University of Vienna)

  • Lena Walch

    (Medical University of Vienna, Max Perutz Labs, Vienna Biocenter)

  • Melania Bruno

    (Medical University of Vienna, Max Perutz Labs, Vienna Biocenter)

  • Rebecca Schneeweiss

    (Medical University of Vienna, Max Perutz Labs, Vienna Biocenter)

  • Juliane Gruber

    (Medical University of Vienna, Max Perutz Labs, Vienna Biocenter)

  • Helena Oberndorfer

    (Medical University of Vienna, Max Perutz Labs, Vienna Biocenter)

  • Emma Frank

    (Medical University of Vienna, Max Perutz Labs, Vienna Biocenter)

  • Xué Strobl

    (Medical University of Vienna, Max Perutz Labs, Vienna Biocenter
    a Doctoral School of the University of Vienna and Medical University of Vienna)

  • Anton Polyansky

    (University of Vienna, Vienna Biocenter)

  • Bojan Zagrovic

    (University of Vienna, Vienna Biocenter)

  • Altuna Akalin

    (The Berlin Institute for Medical Systems Biology, Max Delbrück Center)

  • Dea Slade

    (Medical University of Vienna, Max Perutz Labs, Vienna Biocenter
    Medical University of Vienna
    Medical University of Vienna)

Abstract

Transcription is regulated by a multitude of activators and repressors, which bind to the RNA polymerase II (Pol II) machinery and modulate its progression. Death-inducer obliterator 3 (DIDO3) and PHD finger protein 3 (PHF3) are paralogue proteins that regulate transcription elongation by docking onto phosphorylated serine-2 in the C-terminal domain (CTD) of Pol II through their SPOC domains. Here, we show that DIDO3 and PHF3 form a complex that bridges the Pol II elongation machinery with chromatin and RNA processing factors and tethers Pol II in a phase-separated microenvironment. Their SPOC domains and C-terminal intrinsically disordered regions are critical for transcription regulation. PHF3 and DIDO exert cooperative and antagonistic effects on the expression of neuronal genes and are both essential for neuronal differentiation. In the absence of PHF3, DIDO3 is upregulated as a compensatory mechanism. In addition to shared gene targets, DIDO specifically regulates genes required for lipid metabolism. Collectively, our work reveals multiple layers of gene expression regulation by the DIDO3 and PHF3 paralogues, which have specific, co-regulatory and redundant functions in transcription.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43724-y
    DOI: 10.1038/s41467-023-43724-y
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    References listed on IDEAS

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