Epigenetic regulation of differential HLA-A allelic expression levels

MHC class I expression levels influence the strength of immune responses and represent another variable in determining outcome to disease beyond peptide binding alone. Identification of the HLA loci that vary in allelic expression levels and delineating the mechanism responsible for expression varia...

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Bibliographic Details
Published in:Human molecular genetics 2015-08, Vol.24 (15), p.4268-4275
Main Authors: Ramsuran, Veron, Kulkarni, Smita, O'huigin, Colm, Yuki, Yuko, Augusto, Danillo G, Gao, Xiaojiang, Carrington, Mary
Format: Article
Language:English
Subjects:
Alleles
DNA Methylation - genetics
Epigenesis, Genetic
Gene Expression Regulation
Healthy Volunteers
HLA-A Antigens - biosynthesis
HLA-A Antigens - blood
HLA-A Antigens - genetics
Humans
Immunity, Innate - genetics
RNA, Messenger - biosynthesis
RNA, Messenger - blood
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Summary:MHC class I expression levels influence the strength of immune responses and represent another variable in determining outcome to disease beyond peptide binding alone. Identification of the HLA loci that vary in allelic expression levels and delineating the mechanism responsible for expression variation may provide the opportunity to modify their expression therapeutically. We have examined the expression levels of allelic lineages at the HLA-A locus in a sample of 216 European Americans using a real-time polymerase chain reaction assay, which amplifies all HLA-A lineages specifically with equal efficiency, and observed a gradient of expression that associates with HLA-A allelic lineage (R = 0.6, P = 5 × 10(-25)). DNA methylation of the HLA-A gene appears to contribute to the variation in HLA-A mRNA expression levels, as a significant inverse correlation was observed between HLA-A mRNA expression levels in untreated cells and the degree to which expression is increased after treatment of the cells with a DNA methyltransferase inhibitor (R = 0.6, P = 2.8 × 10(-6)). Further, deep-sequencing and immunoprecipitation assays revealed allelic lineage-specific methylation patterns within the HLA-A promoter region where increased DNA methylation levels correlated significantly with reduced HLA-A expression levels (R = 0.89, P = 3.7 × 10(-9)). These data demonstrate HLA-A allelic lineage-specific variation in expression levels, and DNA methylation as a likely factor in contributing to this variation.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddv158