Dataset Information

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.

SUBMITTER: Majumder P

PROVIDER: S-EPMC3107363 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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

Majumder P P Boss J M JM

Genes and immunity 20110217 4

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- ...[more]

PMID: 21326318

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Project description:BACKGROUND AND OBJECTIVES:Recent evidence suggests that HLA epitope-mismatching at HLA-DQ loci is associated with the development of anti-DQ donor-specific antibodies and adverse graft outcomes. However, the clinical significance of broad antigen HLA-DQ mismatching for graft outcomes is not well examined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Using the United Network Organ Sharing/the Organ Procurement and Transplantation Network (UNOS/OPTN) data, patients with primary kidney transplants performed between 2005 and 2014 were included. Patients were classified as having either zero HLA-DQ mismatches, or one or two HLA-DQ mismatches. Primary outcomes were death-censored graft survival and incidence of acute rejection. RESULTS:A total of 93,782 patients were included. Of these, 22,730 (24%) and 71,052 (76%) received zero and one or two HLA-DQ mismatched kidneys, respectively. After adjusting for variables including HLA-ABDR, HLA-DQ mismatching was associated with a higher risk of graft loss in living kidney donor recipients with an adjusted hazard ratio (HR) of 1.18 (95% confidence interval [95% CI], 1.07 to 1.30; P<0.01), but not in deceased kidney donor recipients (HR, 1.05; 95% CI, 0.98 to 1.12; P=0.18) (P value for interaction <0.01). When taking cold ischemic time into account, HLA-DQ mismatching was associated with a higher risk of graft loss in deceased kidney donor recipients with cold ischemic time ≤17 hours (HR, 1.12; 95% CI, 1.02 to 1.27; P=0.002), but not in deceased kidney donor recipients with cold ischemic time >17 hours (HR, 0.97; 95% CI, 0.88 to 1.06; P=0.49) (P value for interaction <0.01). Recipients with one or two HLA-DQ mismatched kidneys had a higher incidence of acute rejection at 1 year, with adjusted odds ratios of 1.13 (95% CI, 1.03 to 1.23; P<0.01) in deceased donor and 1.14 (95% CI, 1.03 to 1.27; P=0.02) in living donor kidney transplant recipients. Specific donor-DQ mismatches seemed to be associated with the risk of acute rejection and graft failure, whereas others did not. CONCLUSIONS:HLA-DQ mismatching is associated with lower graft survival independent of HLA-ABDR in living donor kidney transplants and deceased donor kidney transplants with cold ischemia time ≤17 hours, and a higher 1-year risk of acute rejection in living and deceased donor kidney transplants.

Dataset Information

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

Publications

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

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