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Accession IconGSE103829

IFIT1 exerts opposing regulatory effects on the inflammatory and interferon gene programs in LPS-activated human macrophages

Organism Icon Homo sapiens
Sample Icon 22 Downloadable Samples
Technology Badge IconIllumina HumanHT-12 V4.0 expression beadchip

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Description
Activation of the TLR4 signaling pathway by LPS leads to induction of both inflammatory and interferon-stimulated genes, however, the mechanisms through which these coordinately activated transcriptional programs are balanced to promote an optimal innate immune response remain poorly understood. In a genome-wide siRNA screen of the LPS-induced TNF- response in macrophages, we identified the interferon-stimulated protein IFIT1 as a negative regulator of the inflammatory gene program. Transcriptional profiling further identified an unexpected positive regulatory role for IFIT1 in type I interferon expression, implicating IFIT1 as a reciprocal modulator of LPS-induced gene classes. We demonstrate that these effects of IFIT1 are mediated through modulation of a Sin3A-HDAC2 transcriptional regulatory complex at LPS-induced gene loci. Beyond the well-studied role of cytosolic IFIT1 in restricting viral replication, our data demonstrate an unappreciated function for nuclear IFIT1 in differential transcriptional regulation of separate branches of the LPS-induced gene program.
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