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

LM. Appel, V. Franke, M. Bruno, I. Grishkovskaya, A. Kasiliauskaite, T. Kaufmann, UE. Schoeberl, MG. Puchinger, S. Kostrhon, C. Ebenwaldner, M. Sebesta, E. Beltzung, K. Mechtler, G. Lin, A. Vlasova, M. Leeb, R. Pavri, A. Stark, A. Akalin, R....

. 2021 ; 12 (1) : 6078. [pub] 20211019

Language English Country Great Britain

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc22003446

Grant support
Wellcome Trust - United Kingdom

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.

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$a The C-terminal domain (CTD) of the largest subunit of RNA polymerase II (Pol II) is a regulatory hub for transcription and RNA processing. Here, we identify PHD-finger protein 3 (PHF3) as a regulator of transcription and mRNA stability that docks onto Pol II CTD through its SPOC domain. We characterize SPOC as a CTD reader domain that preferentially binds two phosphorylated Serine-2 marks in adjacent CTD repeats. PHF3 drives liquid-liquid phase separation of phosphorylated Pol II, colocalizes with Pol II clusters and tracks with Pol II across the length of genes. PHF3 knock-out or SPOC deletion in human cells results in increased Pol II stalling, reduced elongation rate and an increase in mRNA stability, with marked derepression of neuronal genes. Key neuronal genes are aberrantly expressed in Phf3 knock-out mouse embryonic stem cells, resulting in impaired neuronal differentiation. Our data suggest that PHF3 acts as a prominent effector of neuronal gene regulation by bridging transcription with mRNA decay.
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$a Franke, Vedran $u The Berlin Institute for Medical Systems Biology, Max Delbrück Center, Berlin, Germany
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$a Bruno, Melania $u Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna Biocenter (VBC), Vienna, Austria
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$a Grishkovskaya, Irina $u Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Vienna Biocenter (VBC), Vienna, Austria
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$a Kaufmann, Tanja $u Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna Biocenter (VBC), Vienna, Austria
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$a Schoeberl, Ursula E $u National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Brno, Czech Republic
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$a Beltzung, Etienne $u Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna Biocenter (VBC), Vienna, Austria
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$a Djinovic-Carugo, Kristina $u Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Vienna Biocenter (VBC), Vienna, Austria $u Department of Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia
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