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c-Jun controls histone modifications, NF-kappaB recruitment, and RNA polymerase II function to activate the ccl2 gene

Sabine Wolter1, Anneke Doerrie, Axel Weber

  • 1Institute of Pharmacology, Medical School Hannover, Carl-Neuberg Strasse 1, D-30625 Hannover, Germany.

Molecular and Cellular Biology
|April 30, 2008
PubMed

Insights

The transcription factor c-Jun is crucial for regulating inflammatory gene expression, including ccl2 (MCP-1). It controls gene activation through multiple mechanisms involving chromatin modifications and interactions with key proteins like NF-kappaB.

Area of Science:

  • Molecular Biology
  • Immunology
  • Gene Regulation

Background:

  • Interleukin-1 (IL-1) induces expression of inflammatory genes like ccl2 (MCP-1).
  • c-Jun and Jun N-terminal protein kinase (JNK) pathways are critical for this gene induction.
  • The precise role of c-Jun in regulating ccl2 transcription and chromatin dynamics was not fully understood.

Purpose of the Study:

  • To investigate the mechanisms by which c-Jun regulates IL-1-induced ccl2 gene expression.
  • To identify c-Jun binding sites and their functional significance in the ccl2 gene.
  • To elucidate the role of c-Jun in modulating chromatin structure and protein recruitment at the ccl2 locus.

Main Methods:

  • Chromatin immunoprecipitation (ChIP) to identify c-Jun binding sites.
  • Mutational analysis of the ccl2 gene promoter and regulatory regions.
  • Comparison of gene expression in wild-type and c-Jun-deficient cells.
  • Co-immunoprecipitation assays.
  • DNA microarray analysis.

Main Results:

  • Three functional c-Jun binding sites were identified in the murine and human ccl2 genes, with two in the 3' region being critical for IL-1-induced transcription.
  • c-Jun regulates histone modifications (H3 phosphorylation, H3/H4 acetylation) and the recruitment of histone deacetylase 3 (HDAC3), NF-kappaB subunits, and RNA polymerase II to the ccl2 locus.
  • c-Jun physically interacts with p65 NF-kappaB and HDAC3.
  • c-Jun is essential for the full expression of a significant number of IL-1-induced genes, including many inflammatory genes.

Conclusions:

  • c-Jun acts as a critical activator of IL-1-induced inflammatory gene expression, including ccl2.
  • c-Jun employs multiple mechanisms to regulate gene transcription, involving direct DNA binding, modulation of chromatin structure, and protein-protein interactions.
  • These findings highlight the multifaceted role of c-Jun in orchestrating inflammatory responses at the chromatin level.

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