Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

The IL-1beta gene is transcribed from a poised promoter architecture in monocytes

Abstract

Cytokine transcription is usually regulated by transcription factor binding and chromatin remodeling following an inducing signal. By contrast, data herein show the IL-1ss promoter assembles into a "poised" structure, as evidenced by nuclease accessibility and loss of core histones immediately surrounding the transcription start site. Strikingly, these properties do not change upon transcriptional activation by LPS. Furthermore, association of two key transcriptional activators, PU.1 and C/EBPss, is robust pre- and post-stimulation indicating the IL-1ss promoter is packaged into a non-transcribed but poised promoter architecture in cells capable of rapidly inducing IL-1ss. Monocyte stimulation causes recruitment of a third factor, IRF-4, to the IL-1ss enhancer. PU.1 phosphorylation at a CK2 kinase consensus element is required for this recruitment. We show that CK2 phosphorylates PU.1, CK2 inhibitors abrogate IL-1ss induction, and CK2 inducibly associates with the IL-1ss enhancer. Taken together, these data indicate a novel two-step mechanism for IL-1ss transcription: 1) formation of a poised chromatin architecture, and 2) phosphorylation of an enhancer-bound factor that recruits other activators. We propose this poised structure may generally characterize rapidly activated genes.