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Molecular and Cellular Biology, April 2007, p. 2698-2712, Vol. 27, No. 7
0270-7306/07/$08.00+0     doi:10.1128/MCB.00788-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

An Inducible Enhancer Required for Il12b Promoter Activity in an Insulated Chromatin Environment{triangledown}

Liang Zhou,1 Aaron A. Nazarian,1 Jian Xu,1 Dean Tantin,2 Lynn M. Corcoran,3 and Stephen T. Smale1*

Howard Hughes Medical Institute, Molecular Biology Institute, and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California 90095-1662,1 Department of Pathology, University of Utah, Salt Lake City, Utah 84132,2 The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia3

Received 4 May 2006/ Returned for modification 7 June 2006/ Accepted 14 December 2006

Interleukin-12 (IL-12) and IL-23 are heterodimeric cytokines that serve as critical regulators of T helper cell development. The Il12b gene, which encodes the p40 subunit of both IL-12 and IL-23, is expressed in macrophages and dendritic cells following induction by bacterial products. Although the Il12b promoter, like the promoters of most proinflammatory genes, can support transcriptional induction in typical transfection assays, we show that it is not sufficient for transcription in an insulated chromatin environment. Using a DNase I hypersensitivity assay, two potential distal control regions were identified. One region, DNase I-hypersensitive site 1 (HSS1), located 10 kb upstream of the transcription start site, exhibited hypersensitivity only in stimulated macrophages. In an insulated environment, a 105-bp fragment spanning HSS1 was sufficient for transcription when combined with the Il12b promoter. Although several elements are likely to contribute to activity of the endogenous HSS1 enhancer, including an evolutionarily conserved binding site for C/EBP proteins, the only element required for activity in transient- and stable-transfection assays bound Oct-1 and Oct-2, both of which are expressed constitutively in macrophages. Oct-1 and Oct-2 were recruited to the enhancer upon macrophage stimulation, and the Oct site appeared important for nucleosome remodeling at HSS1. These results suggest that the HSS1 enhancer and Oct proteins play central roles in Il12b induction upon macrophage activation.

* Corresponding author. Mailing address: Howard Hughes Medical Institute, UCLA, 6-730 MRL, 675 Charles E. Young Drive South, Los Angeles, CA 90095-1662. Phone: (310) 206-4777. Fax: (310) 206-8623. E-mail: smale{at}mednet.ucla.edu.

{triangledown} Published ahead of print on 22 January 2007.

Molecular and Cellular Biology, April 2007, p. 2698-2712, Vol. 27, No. 7
0270-7306/07/$08.00+0     doi:10.1128/MCB.00788-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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