The Sin3a repressor complex is a master regulator of STAT transcriptional activity.
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.
Department of Medical Protein Research, Vlaams Instituut voor Biotechnologie, 9000 Ghent, Belgium.
Laura
L
Icardi
Raffaele
R
Mori
Viola
V
Gesellchen
Sven
S
Eyckerman
Lode
L
De Cauwer
Judith
J
Verhelst
Koen
K
Vercauteren
Xavier
X
Saelens
Philip
P
Meuleman
Geert
G
Leroux-Roels
Karolien
K
De Bosscher
Michael
M
Boutros
Jan
J
Tavernier
D000107:Acetylation; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D004285:Dogs; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D016174:Hepacivirus / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D009980:Influenza A virus / Q000378:metabolism; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000378:metabolism; D008156:Luciferases; D046228:Microarray Analysis; D018613:Microscopy, Confocal; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D053586:Virus Internalization
D017931:DNA Primers; C494227:IRF9 protein, human; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D008156:Luciferases; D056264:Sin3 Histone Deacetylase and Corepressor Complex