Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4

Document Type

Article

Publication Date

5-11-2006

Abstract

The innate immune system is absolutely required for host defence, but, uncontrolled, it leads to inflammatory disease. This control is mediated, in part, by cytokines that are secreted by macrophages. Immune regulation is extraordinarily complex, and can be best investigated with systems approaches (that is, using computational tools to predict regulatory networks arising from global, high-throughput data sets). Here we use cluster analysis of a comprehensive set of transcriptomic data derived from Toll-like receptor (TLR)-activated macrophages to identify a prominent group of genes that appear to be regulated by activating transcription factor 3 (ATF3), a member of the CREB/ATF family of transcription factors. Network analysis predicted that ATF3 is part of a transcriptional complex that also contains members of the nuclear factor (NF)-κB family of transcription factors. Promoter analysis of the putative ATF3-regulated gene cluster demonstrated an over-representation of closely apposed ATF3 and NF-κB binding sites, which was verified by chromatin immunoprecipitation and hybridization to a DNA microarray. This cluster included important cytokines such as interleukin (IL)-6 and IL-12b. ATF3 and Rel (a component of NF-κB) were shown to bind to the regulatory regions of these genes upon macrophage activation. A kinetic model of II6 and II12b messenger RNA expression as a function of ATF3 and NF-κB promoter binding predicted that ATF3 is a negative regulator of II6 and II12b transcription, and this hypothesis was validated using Atf3-null mice. ATF3 seems to inhibit II6 and II12b transcription by altering chromatin structure, thereby restricting access to transcription factors. Because ATF3 is itself induced by lipopolysaccharide, it seems to regulate TLR-stimulated inflammatory responses as part of a negative-feedback loop. © 2006 Nature Publishing Group.

Publication Source (Journal or Book title)

Nature

First Page

173

Last Page

178

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