Published online 1 February 2006
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Coordinated changes of histone modifications and HDAC mobilization regulate the induction of MHC class II genes by Trichostatin A
1Institute of Molecular Biology and Biotechnology, FORTH Heraklion 71110, Greece 2Department of Biology, University of Crete Heraklion 71110, Greece 3Section of Immunobiology, Yale University School of Medicine New Haven, Connecticut 06520, USA 4Technical University, Institute for Medical Microbiology 81675 Munich, Germany 5Department of Bacteriology, Max-von-Pettenkoffer Institute 80336 Munich, Germany 6Vanderbilt University Medical Center, Division of Cardiovascular Medicine Nashville, Tennessee 37232-6300, USA 7GSF-Research Center for Environment and Health, Institute for Clinical Molecular Biology and Tumor Genetics 81377 Munich, Germany
*To whom correspondence should be addressed. Tel: +30 2810 391165; Fax: +30 2810 391101; Email: papamath{at}imbb.forth.gr
Received October 4, 2005. Revised December 22, 2005. Accepted January 5, 2006.
The deacetylase inhibitor Trichostatin A (TSA) induces the transcription of the Major Histocompatibility Class II (MHC II) DRA gene in a way independent of the master coactivator CIITA. To analyze the molecular mechanisms by which this epigenetic regulator stimulates MHC II expression, we used chromatin immunoprecipitation (ChIP) assays to monitor the alterations in histone modifications that correlate with DRA transcription after TSA treatment. We found that a dramatic increase in promoter linked histone acetylation is followed by an increase in Histone H3 lysine 4 methylation and a decrease of lysine 9 methylation. Fluorescence recovery after photobleaching (FRAP) experiments showed that TSA increases the mobility of HDAC while decreasing the mobility of the class II enhanceosome factor RFX5. These data, in combination with ChIP experiments, indicate that the TSA-mediated induction of DRA transcription involves HDAC relocation and enhanceosome stabilization. In order to gain a genome-wide view of the genes responding to inhibition of deacetylases, we compared the transcriptome of B cells before and after TSA treatment using Affymetrix microarrays. This analysis showed that in addition to the DRA gene, the entire MHC II family and the adjacent histone cluster that are located in chromosome 6p21-22 locus are strongly induced by TSA. A complex pattern of gene reprogramming by TSA involves immune recognition, antiviral, apoptotic and inflammatory pathways and extends the rationale for using Histone Deacetylase Inhibitors (HDACi) to modulate the immune response.
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