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

Lisa Marie Appel; Vedran Franke; Melania Bruno; Irina Grishkovskaya; Aiste Kasiliauskaite; Tanja Kaufmann; Ursula E. Schoeberl; Martin G. Puchinger; Sebastian Kostrhon; Carmen Ebenwaldner; Marek Sebesta; Etienne Beltzung; Karl Mechtler; Gen Lin; Anna Vlasova; Martin Leeb; Rushad Pavri; Alexander Stark; Altuna Akalin; Richard Stefl; Carrie Bernecky; Kristina Djinovic-Carugo; Dea Slade

doi:10.1038/s41467-021-26360-2

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

Lisa Marie Appel, Vedran Franke, Melania Bruno, Irina Grishkovskaya, Aiste Kasiliauskaite, Tanja Kaufmann, Ursula E. Schoeberl, Martin G. Puchinger, Sebastian Kostrhon, Carmen Ebenwaldner, Marek Sebesta, Etienne Beltzung, Karl Mechtler, Gen Lin, Anna Vlasova, Martin Leeb, Rushad Pavri, Alexander Stark, Altuna Akalin, Richard SteflCarrie Bernecky, Kristina Djinovic-Carugo, Dea Slade (Corresponding author)

Publications: Contribution to journal › Article › Peer Reviewed

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.

Original language	English
Article number	6078
Number of pages	24
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-26360-2
Publication status	Published - 19 Oct 2021

Austrian Fields of Science 2012

106002 Biochemistry
106013 Genetics
106023 Molecular biology

Keywords

RNA-POLYMERASE-II
CARBOXY-TERMINAL DOMAIN
CAPPING ENZYME READS
TRANSCRIPTION ELONGATION
STRUCTURAL INSIGHTS
STEM-CELLS
MESSENGER
PHOSPHORYLATION
REVEALS
SPEN

Access to Document

10.1038/s41467-021-26360-2Licence: CC BY 4.0

https://phaidra.univie.ac.at/o:1597526Licence: CC BY 4.0

Cite this

Appel, L. M., Franke, V., Bruno, M., Grishkovskaya, I., Kasiliauskaite, A., Kaufmann, T., Schoeberl, U. E., Puchinger, M. G., Kostrhon, S., Ebenwaldner, C., Sebesta, M., Beltzung, E., Mechtler, K., Lin, G., Vlasova, A., Leeb, M., Pavri, R., Stark, A., Akalin, A., ... Slade, D. (2021). PHF3 regulates neuronal gene expression through the Pol II CTD reader domain SPOC. Nature Communications, 12(1), Article 6078. https://doi.org/10.1038/s41467-021-26360-2

@article{fcc0e2d7c4ec4d16baf72cfced95ce11,

title = "PHF3 regulates neuronal gene expression through the Pol II CTD reader domain SPOC",

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 = "RNA-POLYMERASE-II, CARBOXY-TERMINAL DOMAIN, CAPPING ENZYME READS, TRANSCRIPTION ELONGATION, STRUCTURAL INSIGHTS, STEM-CELLS, MESSENGER, PHOSPHORYLATION, REVEALS, SPEN",

author = "Appel, {Lisa Marie} and Vedran Franke and Melania Bruno and Irina Grishkovskaya and Aiste Kasiliauskaite and Tanja Kaufmann and Schoeberl, {Ursula E.} and Puchinger, {Martin G.} and Sebastian Kostrhon and Carmen Ebenwaldner and Marek Sebesta and Etienne Beltzung and Karl Mechtler and Gen Lin and Anna Vlasova and Martin Leeb and Rushad Pavri and Alexander Stark and Altuna Akalin and Richard Stefl and Carrie Bernecky and Kristina Djinovic-Carugo and Dea Slade",

year = "2021",

month = oct,

day = "19",

doi = "10.1038/s41467-021-26360-2",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "NATURE PUBLISHING GROUP",

number = "1",

}

Appel, LM, Franke, V, Bruno, M, Grishkovskaya, I, Kasiliauskaite, A, Kaufmann, T, Schoeberl, UE, Puchinger, MG, Kostrhon, S, Ebenwaldner, C, Sebesta, M, 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 2021, 'PHF3 regulates neuronal gene expression through the Pol II CTD reader domain SPOC', Nature Communications, vol. 12, no. 1, 6078. https://doi.org/10.1038/s41467-021-26360-2

TY - JOUR

T1 - PHF3 regulates neuronal gene expression through the Pol II CTD reader domain SPOC

AU - Appel, Lisa Marie

AU - Franke, Vedran

AU - Bruno, Melania

AU - Grishkovskaya, Irina

AU - Kasiliauskaite, Aiste

AU - Kaufmann, Tanja

AU - Schoeberl, Ursula E.

AU - Puchinger, Martin G.

AU - Kostrhon, Sebastian

AU - Ebenwaldner, Carmen

AU - Sebesta, Marek

AU - Beltzung, Etienne

AU - Mechtler, Karl

AU - Lin, Gen

AU - Vlasova, Anna

AU - Leeb, Martin

AU - Pavri, Rushad

AU - Stark, Alexander

AU - Akalin, Altuna

AU - Stefl, Richard

AU - Bernecky, Carrie

AU - Djinovic-Carugo, Kristina

AU - Slade, Dea

PY - 2021/10/19

Y1 - 2021/10/19

N2 - 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.

AB - 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.

KW - RNA-POLYMERASE-II

KW - CARBOXY-TERMINAL DOMAIN

KW - CAPPING ENZYME READS

KW - TRANSCRIPTION ELONGATION

KW - STRUCTURAL INSIGHTS

KW - STEM-CELLS

KW - MESSENGER

KW - PHOSPHORYLATION

KW - REVEALS

KW - SPEN

UR - http://www.scopus.com/inward/record.url?scp=85117730956&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-26360-2

DO - 10.1038/s41467-021-26360-2

M3 - Article

C2 - 34667177

AN - SCOPUS:85117730956

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 6078

ER -

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

Abstract

Austrian Fields of Science 2012

Keywords

Access to Document

Other files and links

Fingerprint

Cite this