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Molecular and Cellular Biology, July 2008, p. 4407-4423, Vol. 28, No. 13
0270-7306/08/$08.00+0     doi:10.1128/MCB.00535-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

c-Jun Controls Histone Modifications, NF-B Recruitment, and RNA Polymerase II Function To Activate the ccl2 Gene ^,

Institute of Pharmacology, Medical School Hannover, Carl-Neuberg Strasse 1, D-30625 Hannover,¹ Rudolph Buchheim Institute of Pharmacology, Justus Liebig University Giessen, D-35392 Giessen, Germany,³ Institute of Molecular Pathology, Vienna A-1030, Austria²

Received 28 March 2007/ Returned for modification 26 June 2007/ Accepted 11 April 2008

Interleukin-1 (IL-1)-induced mRNA expression of ccl2 (also called MCP-1), a prototypic highly regulated inflammatory gene, is severely suppressed in cells lacking c-Jun or Jun N-terminal protein kinase 1 (JNK1)/JNK2 genes and is only partially restored in cells expressing a c-Jun(SS63/73AA) mutant protein. We used chromatin immunoprecipitation to identify three c-Jun-binding sites located in the far 5' region close to the transcriptional start site and in the far 3' region of murine and human ccl2 genes. Mutational analysis revealed that the latter two sites contribute to ccl2 transcription in response to the presence of IL-1 or of ectopically expressed c-Jun-ATF-2 dimers. Further experiments comparing wild-type and c-Jun-deficient cells revealed that c-Jun regulates Ser10 phosphorylation of histone H3, acetylation of histones H3 and H4, and recruitment of histone deacetylase 3 (HDAC3), NF-B subunits, and RNA polymerase II across the ccl2 locus. c-Jun also coimmunoprecipitated with p65 NF-B and HDAC3. Based on DNA microarray analysis, c-Jun was required for full expression of 133 out of 162 IL-1-induced genes. For inflammatory genes, these data support the idea of an activator function of c-Jun that is executed by multiple mechanisms, including phosphorylation-dependent interaction with p65 NF-B and HDAC3 at the level of chromatin.

Published ahead of print on 28 April 2008.

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