title: DNA methylation dysregulates and silences the HLA-DQ locus by altering chromatin architecture.
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.
authors.affiliation: Department of Microbiology and Immunology, Emory University School Of Medicine, Atlanta, GA 30322, USA.
authors.forename: P
authors.initials: P
authors.lastname: Majumder
authors.forename: J M
authors.initials: JM
authors.lastname: Boss
mesh_terms: D000076246:CCCTC-Binding Factor; D002460:Cell Line; D002843:Chromatin / Q000235:genetics* / Q000276:immunology; D018899:CpG Islands; D019175:DNA Methylation; D020868:Gene Silencing; D056426:Genetic Loci; D006683:HLA-DQ Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D002843:Chromatin; D006683:HLA-DQ Antigens; D012097:Repressor Proteins