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

Tyrosine phosphorylation is a hallmark for activation of proteins, but their transcriptional activity also depends on other secondary modifications. Type I IFNs can activate both the ISGF3 complex and but with cell-specific, selective triggering of only the ISGF3 transcriptional program. Following a genome-wide screen, we identified the SIN3 transcription regulator homolog A (Sin3a) as an important mediator of this transcriptional repression. Sin3a directly interacts with and promotes its deacetylation. SIN3A silencing results in a prolonged nuclear retention of activated duanyu18133 and enhances its recruitment to the SOCS3 promoter, concomitant with histone hyperacetylation and enhanced 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 transcriptional switch.

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