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DNA methylation dysregulates and silences the HLA-DQ locus....

kday

Senior Member
Messages
369
Medical journal in Nature. Is this relevant, and if so, what does it mean? I'm obviously not a science expert. Thanks.

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Genes and Immunity advance online publication 17*February*2011; doi: 10.1038/gene.2010.77

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.

http://www.nature.com/gene/journal/vaop/ncurrent/abs/gene201077a.html
 

LaurieL

Senior Member
Messages
447
Location
Midwest
kday
DNA methylation dysregulates and silences the HLA-DQ locus....

Medical journal in Nature. Is this relevant, and if so, what does it mean? I'm obviously not a science expert. Thanks.

--------------

Genes and Immunity advance online publication 17*February*2011; doi: 10.1038/gene.2010.77

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.

http://www.nature.com/gene/journal/v...ne201077a.html

Kday,

This particular source is referring to the promoter genes and the abnormal hypermethylation they acquire in cancer. It is this concept in which may promote further understanding of the tumor suppressor genes and a future target in cancer therapies. As I recall, there are approximately 7 processes including hypermethylation in which tumor genesis and cancer can take hold. I can't name all seven processes.

It is the promoter genes when acquiring abnormal hypermethylation that silence transcription, and there for silence DNA chromatin, affecting the HLA DR, DQ genotypes. It is important to understand chromatin and its functions, and without normal methylation such as we discuss here on this forum, lack of normal methylation can equally cause the expression of unwanted sequences.

Laurie