Publication details

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

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Authors

APPEL Lisa-Marie FRANKE Vedran BRUNO Melania GRISHKOVSKAYA Irina KASILIAUSKAITE Aiste KAUFMANN Tanja SCHOEBERL Ursula E. PUCHINGER Martin G. KOSTRHON Sebastian EBENWALDNER Carmen ŠEBESTA Marek BELTZUNG Etienne MECHTLER Karl LIN Gen VLASOVA Anna LEEB Martin PAVRI Rushad STARK Alexander AKALIN Altuna ŠTEFL Richard BERNECKY Carrie DJINOVIC-CARUGO Kristina SLADE Dea

Year of publication 2021
Type Article in Periodical
Magazine / Source Nature Communications
MU Faculty or unit

Central European Institute of Technology

Citation
Web https://www.nature.com/articles/s41467-021-26360-2
Doi http://dx.doi.org/10.1038/s41467-021-26360-2
Keywords Gene expression; Neural stem cells; Transcription; X-ray crystallography
Description 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. Here the authors identify PHF3 SPOC domain as a reader of the phosphorylated RNA polymerase II (Pol II) C-terminal domain. They show that PHF3 clusters with Pol II complexes in cells, drives phase separation of Pol II in vitro, and regulates neuronal gene expression and neuronal differentiation.
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