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

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Item Type:

Article

Title:

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

Creators Name:

Appel, L.M. and Franke, V. and Bruno, M. and Grishkovskaya, I. and Kasiliauskaite, A. and Kaufmann, T. and Schoeberl, U.E. and Puchinger, M.G. and Kostrhon, S. and Ebenwaldner, C. and Sebesta, M. and Beltzung, E. and Mechtler, K. and Lin, G. and Vlasova, A. and Leeb, M. and Pavri, R. and Stark, A. and Akalin, A. and Stefl, R. and Bernecky, C. and Djinovic-Carugo, K. and Slade, D.

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.

Keywords:

Cell Line, Gene Expression Regulation, Gene Knockdown Techniques, Genetic Transcription, Knockout Mice, Neurons, Phosphorylation, Post-Transcriptional RNA Processing, Protein Domains, RNA, RNA Polymerase II, RNA Stability, Transcription Factors, Animals, Mice

Source:

Nature Communications

ISSN:

2041-1723

Publisher:

Nature Publishing Group

Volume:

Number:

Page Range:

6078

Date:

19 October 2021