Gene-specific Requirement of a Nuclear Protein, IκB-ζ, for Promoter Association of Inflammatory Transcription Regulators

Susumu Matsuo,Soh Yamazaki,Tatsushi Muta,Masahiro Yamamoto,Shizuo Akira,Koichiro Takeshige

doi:10.1074/jbc.m802148200

Abstract

Expression of many inflammatory genes is induced through activation of the transcription factor NF-kappaB. In contrast to the advanced understanding of cytoplasmic control of NF-kappaB activation, its regulation in the nucleus has not been fully understood despite its importance in selective gene expression. We previously identified an inducible nuclear protein, IkappaB-zeta, and demonstrated that this molecule is indispensable for the expression of a group of NF-kappaB-regulated genes. In this study, we established a unique gene induction system, in which IkappaB-zeta is expressed independently of inflammatory stimuli, to specifically investigate the molecular basis underlying IkappaB-zeta-mediated gene activation. We show that in the presence of IkappaB-zeta other primary response genes are dispensable for the expression of the target secondary response genes. ChIP analyses revealed that IkappaB-zeta is required for stimulus-induced recruitment of NF-kappaB onto the target promoter in a gene-specific manner. Surprisingly, IkappaB-zeta is also necessary for the gene-selective promoter recruitment of another inflammatory transcription factor, C/EBPbeta, and the chromatin remodeling factor Brg1. We propose a new gene regulatory mechanism underlying the selective expression of inflammatory genes.

Highlights

Many cellular responses are mediated by orchestrated gene expression
It was proposed that inflammatory genes could be categorized into two groups based on their requirement of de novo protein synthesis for induction [6, 7]
I␬B-␨ is encoded by a primary response gene, Nfkbiz, and its induction depends on nuclear factor (NF)-␬B activation (14 –16), suggesting that I␬B-␨-regulated genes are induced via a two-step machinery

Summary

Introduction

Many cellular responses are mediated by orchestrated gene expression. When cells are exposed to diverse inflammatory stimuli, such as microbial components, a large number of genes are induced to elicit inflammatory responses. We have shown that TNF-␣ induced the transcription of the Nfkbiz gene but did not stabilize I␬B-␨ mRNA, indicating that the stimulus-specific expression of I␬B-␨ is determined post-transcriptionally [15] It is still unknown how I␬B-␨ is involved in the transcriptional activation of its target genes. Our ChIP experiments revealed the gene-specific requirement of I␬B-␨ for the promoter recruitment of NF-␬B and other transcription regulators involved in inflammatory responses. These findings suggest that I␬B-␨ plays a critical role in the selective gene expression by controlling the association of key transcription regulators with target promoters in the nucleus

Methods

Results

Conclusion