Original Article

Genes and Immunity (2011) 12, 291–299; doi:10.1038/gene.2010.77; published online 17 February 2011

DNA methylation dysregulates and silences the HLA-DQ locus by altering chromatin architecture

P Majumder1 and J M Boss1

1Department of Microbiology and Immunology, Emory University School Of Medicine, Atlanta, GA, USA

Correspondence: Dr JM Boss, Department of Microbiology and Immunology, Emory University School Of Medicine, 1510 Clifton Road, Atlanta, GA 30322, USA. E-mail: jmboss@emory.edu

Received 14 July 2010; Revised 30 August 2010; Accepted 31 August 2010; Published online 17 February 2011.

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Abstract

The major histocompatibility complex class II (MHC-II) locus encodes a cluster of highly polymorphic genes HLA-DR, -DQ and -DP that are co-expressed in mature B lymphocytes. Two cell lines were established over 30 years ago from a patient diagnosed with acute lymphocytic leukemia. Laz221 represented the leukemic cells of the patient; whereas Laz388 represented the normal B cells of the patient. Although Laz388 expressed both HLA-DR and HLA-DQ surface and gene products, Laz221 expressed only HLA-DR genes. The discordant expression of HLA-DR and HLA-DQ genes was due to epigenetic silencing of the HLA-DQ region CCCTC transcription factor (CTCF)-binding insulators that separate the MHC-II sub-regions by DNA methylation. These epigenetic modifications resulted in the loss of binding of the insulator protein CTCF to the HLA-DQ flanking insulator regions and the MHC-II-specific transcription factors to the HLA-DQ promoter regions. These events led to the inability of the HLA-DQ promoter regions to interact with flanking insulators that control HLA-DQ expression. Inhibition of DNA methylation by treatment with 5′-deoxyazacytidine reversed each of these changes and restored expression of the HLA-DQ locus. These results highlight the consequence of disrupting an insulator within the MHC-II region and may be a normal developmental mechanism or one used by tumor cells to escape immune surveillance.

Keywords:

MHC; gene regulation; transcription; DNA methylation; chromatin