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 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.
Cancer Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research Incorporated, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA and Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02139, USA.
Veron
V
Ramsuran
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02139, USA.
Smita
S
Kulkarni
Cancer Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research Incorporated, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA and.
Colm
C
O'huigin
Cancer Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research Incorporated, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA and.
Yuko
Y
Yuki
Cancer Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research Incorporated, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA and Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02139, USA.
Danillo G
DG
Augusto
Cancer Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research Incorporated, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA and.
Xiaojiang
X
Gao
Cancer Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research Incorporated, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA and Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02139, USA carringm@mail.nih.gov.
Mary
M
Carrington
D000483:Alleles; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D015234:HLA-A Antigens / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D064368:Healthy Volunteers; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000097:blood
D015234:HLA-A Antigens; D012333:RNA, Messenger