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

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

doi:10.1101/2020.02.11.943159

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bioRxiv · 10.1101/2020.02.11.943159

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

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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 new CTD-binding factor that negatively regulates transcription and mRNA stability. The PHF3 SPOC domain preferentially binds to CTD repeats phosphorylated on Serine-2 and PHF3 tracks with Pol II across the length of genes. PHF3 competes with TFIIS for Pol II binding through its TFIIS-like domain (TLD), thus inhibiting TFIIS-mediated rescue of backtracked Pol II. PHF3 knock-out or PHF3 SPOC deletion in human cells result in gene upregulation and a global 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 is a prominent effector of neuronal gene regulation at the interface of transcription elongation and mRNA decay.

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Appel, L.-M., Franke, V., Bruno, M., Grishkovskaya, I., Kasiliauskaite, A., Schoeberl, U. E., Puchinger, M. G., Kostrhon, S., Beltzung, E., Mechtler, K., Lin, G., Vlasova, A., Leeb, M., Pavri, R., Stark, A., Akalin, A., Stefl, R., Bernecky, C., Djinovic-Carugo, K., Slade, D.. 2020-02-12. PHF3 regulates neuronal gene expression through the new Pol II CTD reader domain SPOC. https://doi.org/10.1101/2020.02.11.943159

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