Epigenetic regulation of differential HLA-A allelic expression levels
Epigenetic regulation of differential HLA-A allelic expression levels
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DOI：
10.1093/hmg/ddv158
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发表时间：
2015-08-01
影响因子：
3.5
通讯作者：
Carrington, Mary
中科院分区：
文献类型：
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作者：
Ramsuran, Veron;Kulkarni, Smita;Carrington, Mary
MHC-I类分子的表达水平影响免疫反应的强度，并代表着决定疾病结局的另一个变量，而不仅仅是肽结合。识别等位基因表达水平不同的人类白细胞抗原基因座，并阐明导致表达变化的机制，可能为在治疗上改变其表达提供机会。我们用实时聚合酶链式反应技术检测了216例欧洲裔美国人的人类白细胞抗原A基因座等位基因谱系的表达水平，该方法以同样的效率特异性地扩增了所有的人类白细胞抗原A基因谱系，并观察到了与人类白细胞抗原A等位基因谱系相关的表达梯度(R=0.6，P=5×10(-25))。人类白细胞抗原-A基因的DNA甲基化似乎是导致人类白细胞抗原-A基因表达水平变化的原因之一，因为未经处理的细胞的人类白细胞抗原-A基因的表达水平与DNA甲基转移酶抑制剂处理后的表达增加程度呈显著负相关(R=0.6，P=2.8×10(-6))。此外，深度测序和免疫沉淀分析显示，在人类白细胞抗原-A启动子区存在等位基因谱系特异性甲基化模式，其中DNA甲基化水平升高与人类白细胞抗原-A表达水平降低显著相关(R=0.89，P=3.7×10(-9))。这些数据表明，人类白细胞抗原-A等位基因谱系在表达水平上存在差异，DNA甲基化可能是导致这种差异的一个因素。
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 x 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 x 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 x 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.