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

• Type of Material: Article
• Authors: Parimal Majumder, Emory University; Jeremy Boss, Emory University
• Language: English
• Date: 2011-06
• Publisher: Nature Publishing Group: Open Access Hybrid Model Option B
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 Macmillan Publishers Limited All rights reserved
• Final Published Version (URL): http://www.nature.com/gene/journal/v12/n4/full/gene201077a.html
• Title of Journal or Parent Work: Genes and Immunity
• ISSN: 1466-4879
• Volume: 12
• Issue: 4
• Start Page: 291
• End Page: 299
• Grant/Funding Information: National Institute of General Medical Sciences : NIGMS; This work was supported by NIH grant GM47310.
• Keywords: transcription; gene regulation; DNA methylation; MHC; chromatin
• Research Categories: Biology, Genetics; Health Sciences, Immunology

Abstract

The 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. Whereas 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 CTCF-binding insulators that separate the MHC-II subregions 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.