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The transcription factor RFX protects MHC class II genes against epigenetic silencing by DNA methylation

Seguin-Estevez, Queralt
De Palma, Raffaele
Picard, Capucine
Tagliamacco, Augusto
Abbate, Gianfranco
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Published in Journal of Immunology. 2009, vol. 183, no. 4, p. 2545-2553
Abstract 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-gamma.
Keywords B-Lymphocyte Subsets/immunology/metabolismCell LineCell Line, TumorCells, CulturedDNA Methylation/ immunologyDNA-Binding Proteins/deficiency/genetics/ physiologyEnhancer Elements, Genetic/immunologyGene Silencing/ immunologyHLA-D Antigens/ biosynthesis/ geneticsHumansNuclear Proteins/deficiency/genetics/physiologyPromoter Regions, Genetic/immunologyTrans-Activators/deficiency/genetics/physiologyTranscription Factors/deficiency/genetics/ physiology
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PMID: 19620312
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