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

Research output: Contribution to journalArticle

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 languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number30
Pages (from-to)12058-63
Number of pages6
ISSN0027-8424
DOIs
Publication statusPublished - 24-Jul-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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