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

Genes & Immunity volume 12, pages 291–299 (2011)Cite this article

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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.

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Acknowledgements

We thank Dr C Scharer for aiding with the development of the MeDIP assay and his comments of the work. We thank and acknowledge the technical support for this project from Royce Butler. This work was supported by NIH grant GM47310.

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

    P Majumder & J M Boss

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Correspondence to J M Boss.

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Majumder, P., Boss, J. DNA methylation dysregulates and silences the HLA-DQ locus by altering chromatin architecture. Genes Immun 12, 291–299 (2011). https://doi.org/10.1038/gene.2010.77

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