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

Johannes Benedum, Vedran Franke, Lisa-Marie Appel, Lena Walch, Melania Bruno, Rebecca Schneeweiss, Juliane Gruber, Helena Oberndorfer, Emma Frank, Xué Strobl, Anton Polyansky, Bojan Zagrovic, Altuna Akalin and Dea Slade ()
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Johannes Benedum: Medical University of Vienna, Max Perutz Labs, Vienna Biocenter
Vedran Franke: The Berlin Institute for Medical Systems Biology, Max Delbrück Center
Lisa-Marie Appel: Medical University of Vienna, Max Perutz Labs, Vienna Biocenter
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
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

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43724-y

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