The Sin3a repressor complex is a master regulator of STAT transcriptional activity

Laura Icardi; Raffaele Mori; Viola Gesellchen; Sven Eyckerman; Lode De Cauwer; Judith Verhelst; Koen Vercauteren; Xavier Saelens; Philip Meuleman; Geert Leroux-Roels; Karolien De Bosscher; Michael Boutros; Jan Tavernier

doi:10.1073/pnas.1206458109

The Sin3a repressor complex is a master regulator of STAT transcriptional activity

Laura Icardi, Raffaele Mori, Viola Gesellchen, Sven Eyckerman, Lode De Cauwer, Judith Verhelst, Koen Vercauteren, Xavier Saelens, Philip Meuleman, Geert Leroux-Roels, Karolien De Bosscher, Michael Boutros, Jan Tavernier

Clinical Virology

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Abstract

Tyrosine phosphorylation is a hallmark for activation of STAT proteins, but their transcriptional activity also depends on other secondary modifications. Type I IFNs can activate both the ISGF3 (STAT1:STAT2:IRF9) complex and STAT3, but with cell-specific, selective triggering of only the ISGF3 transcriptional program. Following a genome-wide RNAi screen, we identified the SIN3 transcription regulator homolog A (Sin3a) as an important mediator of this STAT3-targeted transcriptional repression. Sin3a directly interacts with STAT3 and promotes its deacetylation. SIN3A silencing results in a prolonged nuclear retention of activated STAT3 and enhances its recruitment to the SOCS3 promoter, concomitant with histone hyperacetylation and enhanced STAT3-dependent transcription. Conversely, Sin3a is required for ISGF3-dependent gene transcription and for an efficient IFN-mediated antiviral protection against influenza A and hepatitis C viruses. The Sin3a complex therefore acts as a context-dependent ISGF3/STAT3 transcriptional switch.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	109
Issue number	30
Pages (from-to)	12058-12063
Number of pages	6
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.1206458109
Publication status	Published - 2012

Keywords

Acetylation
Animals
Blotting, Western
Cell Line
Chromatin Immunoprecipitation
DNA Primers/genetics
Dogs
Flow Cytometry
Gene Expression Regulation/genetics
Hepacivirus/metabolism
Humans
Immunoprecipitation
Influenza A virus/metabolism
Interferon-Stimulated Gene Factor 3, gamma Subunit/metabolism
Luciferases
Microarray Analysis
Microscopy, Confocal
RNA Interference
Real-Time Polymerase Chain Reaction
Repressor Proteins/metabolism
STAT3 Transcription Factor/metabolism
Sin3 Histone Deacetylase and Corepressor Complex
Virus Internalization

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2012pnas12058Final published version, 828 KBLicence: Other

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Icardi, L., Mori, R., Gesellchen, V., Eyckerman, S., De Cauwer, L., Verhelst, J., Vercauteren, K., Saelens, X., Meuleman, P., Leroux-Roels, G., De Bosscher, K., Boutros, M., & Tavernier, J. (2012). The Sin3a repressor complex is a master regulator of STAT transcriptional activity. Proceedings of the National Academy of Sciences of the United States of America, 109(30), 12058-12063. https://doi.org/10.1073/pnas.1206458109

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title = "The Sin3a repressor complex is a master regulator of STAT transcriptional activity",

abstract = "Tyrosine phosphorylation is a hallmark for activation of STAT proteins, but their transcriptional activity also depends on other secondary modifications. Type I IFNs can activate both the ISGF3 (STAT1:STAT2:IRF9) complex and STAT3, but with cell-specific, selective triggering of only the ISGF3 transcriptional program. Following a genome-wide RNAi screen, we identified the SIN3 transcription regulator homolog A (Sin3a) as an important mediator of this STAT3-targeted transcriptional repression. Sin3a directly interacts with STAT3 and promotes its deacetylation. SIN3A silencing results in a prolonged nuclear retention of activated STAT3 and enhances its recruitment to the SOCS3 promoter, concomitant with histone hyperacetylation and enhanced STAT3-dependent transcription. Conversely, Sin3a is required for ISGF3-dependent gene transcription and for an efficient IFN-mediated antiviral protection against influenza A and hepatitis C viruses. The Sin3a complex therefore acts as a context-dependent ISGF3/STAT3 transcriptional switch.",

keywords = "Acetylation, Animals, Blotting, Western, Cell Line, Chromatin Immunoprecipitation, DNA Primers/genetics, Dogs, Flow Cytometry, Gene Expression Regulation/genetics, Hepacivirus/metabolism, Humans, Immunoprecipitation, Influenza A virus/metabolism, Interferon-Stimulated Gene Factor 3, gamma Subunit/metabolism, Luciferases, Microarray Analysis, Microscopy, Confocal, RNA Interference, Real-Time Polymerase Chain Reaction, Repressor Proteins/metabolism, STAT3 Transcription Factor/metabolism, Sin3 Histone Deacetylase and Corepressor Complex, Virus Internalization",

author = "Laura Icardi and Raffaele Mori and Viola Gesellchen and Sven Eyckerman and {De Cauwer}, Lode and Judith Verhelst and Koen Vercauteren and Xavier Saelens and Philip Meuleman and Geert Leroux-Roels and {De Bosscher}, Karolien and Michael Boutros and Jan Tavernier",

note = "FTX",

year = "2012",

doi = "10.1073/pnas.1206458109",

language = "English",

volume = "109",

pages = "12058--12063",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

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Icardi, L, Mori, R, Gesellchen, V, Eyckerman, S, De Cauwer, L, Verhelst, J, Vercauteren, K, Saelens, X, Meuleman, P, Leroux-Roels, G, De Bosscher, K, Boutros, M & Tavernier, J 2012, 'The Sin3a repressor complex is a master regulator of STAT transcriptional activity', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 30, pp. 12058-12063. https://doi.org/10.1073/pnas.1206458109

TY - JOUR

T1 - The Sin3a repressor complex is a master regulator of STAT transcriptional activity

AU - Icardi, Laura

AU - Mori, Raffaele

AU - Gesellchen, Viola

AU - Eyckerman, Sven

AU - De Cauwer, Lode

AU - Verhelst, Judith

AU - Vercauteren, Koen

AU - Saelens, Xavier

AU - Meuleman, Philip

AU - Leroux-Roels, Geert

AU - De Bosscher, Karolien

AU - Boutros, Michael

AU - Tavernier, Jan

N1 - FTX

PY - 2012

Y1 - 2012

N2 - Tyrosine phosphorylation is a hallmark for activation of STAT proteins, but their transcriptional activity also depends on other secondary modifications. Type I IFNs can activate both the ISGF3 (STAT1:STAT2:IRF9) complex and STAT3, but with cell-specific, selective triggering of only the ISGF3 transcriptional program. Following a genome-wide RNAi screen, we identified the SIN3 transcription regulator homolog A (Sin3a) as an important mediator of this STAT3-targeted transcriptional repression. Sin3a directly interacts with STAT3 and promotes its deacetylation. SIN3A silencing results in a prolonged nuclear retention of activated STAT3 and enhances its recruitment to the SOCS3 promoter, concomitant with histone hyperacetylation and enhanced STAT3-dependent transcription. Conversely, Sin3a is required for ISGF3-dependent gene transcription and for an efficient IFN-mediated antiviral protection against influenza A and hepatitis C viruses. The Sin3a complex therefore acts as a context-dependent ISGF3/STAT3 transcriptional switch.

AB - Tyrosine phosphorylation is a hallmark for activation of STAT proteins, but their transcriptional activity also depends on other secondary modifications. Type I IFNs can activate both the ISGF3 (STAT1:STAT2:IRF9) complex and STAT3, but with cell-specific, selective triggering of only the ISGF3 transcriptional program. Following a genome-wide RNAi screen, we identified the SIN3 transcription regulator homolog A (Sin3a) as an important mediator of this STAT3-targeted transcriptional repression. Sin3a directly interacts with STAT3 and promotes its deacetylation. SIN3A silencing results in a prolonged nuclear retention of activated STAT3 and enhances its recruitment to the SOCS3 promoter, concomitant with histone hyperacetylation and enhanced STAT3-dependent transcription. Conversely, Sin3a is required for ISGF3-dependent gene transcription and for an efficient IFN-mediated antiviral protection against influenza A and hepatitis C viruses. The Sin3a complex therefore acts as a context-dependent ISGF3/STAT3 transcriptional switch.

KW - Acetylation

KW - Animals

KW - Blotting, Western

KW - Cell Line

KW - Chromatin Immunoprecipitation

KW - DNA Primers/genetics

KW - Dogs

KW - Flow Cytometry

KW - Gene Expression Regulation/genetics

KW - Hepacivirus/metabolism

KW - Humans

KW - Immunoprecipitation

KW - Influenza A virus/metabolism

KW - Interferon-Stimulated Gene Factor 3, gamma Subunit/metabolism

KW - Luciferases

KW - Microarray Analysis

KW - Microscopy, Confocal

KW - RNA Interference

KW - Real-Time Polymerase Chain Reaction

KW - Repressor Proteins/metabolism

KW - STAT3 Transcription Factor/metabolism

KW - Sin3 Histone Deacetylase and Corepressor Complex

KW - Virus Internalization

U2 - 10.1073/pnas.1206458109

DO - 10.1073/pnas.1206458109

M3 - Article

C2 - 22783022

SN - 0027-8424

VL - 109

SP - 12058

EP - 12063

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 30

ER -

The Sin3a repressor complex is a master regulator of STAT transcriptional activity

Abstract

Keywords

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