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* University of Geneva, Faculty of Medicine, Geneva, Switzerland;
Department of Clinical and Experimental Medicine, Second University of Naples, Naples, Italy;
Immunology and Transplant Unit, Geneva University Hospital, Geneva, Switzerland;
Study Center of Primary Immunodeficiencies, Necker Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France;
¶ Transplant Immunology Unit, Department of Transplantation, S. Martino Hospital, Genoa, Italy; and
|| Blood Research Institute, Blood Center of Wisconsin, Milwaukee WI 53201
Classical and nonclassical MHC class II (MHCII) genes are coregulated by the transcription factor RFX (regulatory factor X) and the transcriptional coactivator CIITA. RFX coordinates the assembly of a multiprotein "enhanceosome" complex on MHCII promoters. This enhanceosome serves as a docking site for the binding of CIITA. Whereas the role of the enhanceosome in recruiting CIITA is well established, little is known about its CIITA-independent functions. A novel role of the enhanceosome was revealed by the analysis of HLA-DOA expression in human MHCII-negative B cell lines lacking RFX or CIITA. HLA-DOA was found to be reactivated by complementation of CIITA-deficient but not RFX-deficient B cells. Silencing of HLA-DOA was associated with DNA methylation at its promoter, and was relieved by the demethylating agent 5-azacytidine. Surprisingly, DNA methylation was also established at the HLA-DRA and HLA-DQB loci in RFX-deficient cells. This was a direct consequence of the absence of RFX, as it could be reversed by restoring RFX function. DNA methylation at the HLA-DOA, HLA-DRA, and HLA-DQB promoters was observed in RFX-deficient B cells and fibroblasts, but not in CIITA-deficient B cells and fibroblasts, or in wild-type fibroblasts, which lack CIITA expression. These results indicate that RFX and/or enhanceosome assembly plays a key CIITA-independent role in protecting MHCII promoters against DNA methylation. This function is likely to be crucial for retaining MHCII genes in an open chromatin configuration permissive for activation in MHCII-negative cells, such as the precursors of APC and nonprofessional APC before induction with IFN-
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Work in the laboratory of W. Reith was supported by the Swiss National Science Foundation, The Swiss Multiple Sclerosis Society, The Geneva Cancer League, and the National Center of Competence in Research–Neural Plasticity and Repair (NCCR-NEURO). Work in the laboratory of R. de Palma was supported by Grants 2005064784_004 and 2007XKCCWF_004 from the Ministero dell’Istruzione dell’Università e della Ricerca. Work in the laboratory of A. Nocera was in part supported by a scholarship to A. Tagliamacco provided by the S. Martino Hospital, Genoa, Italy.
2 Q.S.-E., R.P., A.N., and W.R. contributed equally to this study.
3 Current address: Regulatory Biology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037.
4 Address correspondence and reprint requests to Dr. Walter Reith, Department of Pathology and Immunology, University of Geneva, Faculty of Medicine, 1 rue Michel-Servet, CH-1211, Geneva, Switzerland. E-mail address: Walter.Reith{at}unige.ch
5 Abbreviations used in this paper: MHCII, MHC class II; BLS, bare lymphocyte syndrome; ChIP, chromatin immunoprecipitation; CREB, cAMP responsive element-binding protein; cTEC, cortical thymic epithelial cells; DC, dendritic cell; 5AC, 5-azacytidine; mTEC, medullary thymic epithelial cell; NF-Y, nuclear factor Y; RFX, regulatory factor X; TSA, trichostatin A; TSS, transcription start site; WT, wild type.
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