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Rapid induction of expression by LPS is accompanied by favorable chromatin and rapid binding of c-Jun.

The response to infection is managed in mammals by a coordinated immune response. Innate responses are rapid and hard wired and have been demonstrated to be regulated at the level of chromatin accessibility. This study examined primary human monocyte responses to LPS as a model of innate responses to bacteria. We utilized inhibitors of chromatin modifying enzymes to understand the inter-relationships of the chromatin complexes regulating transcription. Multiplex digital gene detection was utilized to quantitate changes in mRNA levels for genes induced by LPS. In the first 30 min, genes that were highly induced by LPS as a group exhibited minimal effect of the chemical inhibitors of chromatin modifications. At 60 min, the more highly expressed genes were markedly more inhibitable. The effects of the inhibitors were almost entirely concordant in spite of different mechanisms of action. Two focus groups of genes with either high LPS inducibility at 30 min or high LPS inducibility at 60 min (but not at 30 min) were further examined by ChIP assay. NFκB p65 binding was increased at the promoters of 30- and 60-min highly inducible genes equivalently. Binding of c-Jun was increased after LPS in the 30-min inducible gene set but not the 60-min inducible gene set. H3K4me3 and H4ac were not detectably altered by LPS stimulation. Baseline H3K4me3 and H4ac were higher in the 30-min highly inducible gene set compared to the 60-min highly inducible gene set. NFκB and JNK inhibitors led to diminished H4ac after LPS. The effects of DRB and C646 were greater for LPS-induced IL6 transcription at 30 min and LPS-stimulated H4ac compared to TNF where transcription was largely unaffected by the inhibitors. In conclusion, genes with very rapidly induced expression after LPS exhibited more favorable chromatin characteristics at baseline and were less inhibitable than genes induced at the later time points.

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