Ethnicity-specific epigenetic variation in naïve CD4+ T cells and the susceptibility to autoimmunity.
Ethnicity-specific epigenetic variation in naïve CD4+ T cells and the susceptibility to autoimmunity.
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DOI：
10.1186/s13072-015-0037-1
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发表时间：
2015
影响因子：
3.9
通讯作者：
Sawalha AH
中科院分区：
文献类型：
--
作者：
Coit P;Ognenovski M;Gensterblum E;Maksimowicz-McKinnon K;Wren JD;Sawalha AH
遗传和表观遗传变异导致自身免疫性疾病的易感性和发病机制。 T 细胞在多种自身免疫性疾病中发挥着重要作用，其中包括狼疮，狼疮在非洲人后裔中更为常见且更为严重。为了研究不同种族之间 T 细胞固有的表观遗传差异，我们对健康非裔美国人和欧洲裔美国人的幼稚 CD4+ T 细胞的全基因组 DNA 甲基化模式进行了表征，然后在狼疮患者中证实了我们的发现。首次揭示了幼稚 CD4+ T 细胞中令人印象深刻的种族特异性 DNA 甲基化聚类。健康非裔美国人的低甲基化位点显着富含促凋亡和促炎症基因。我们还发现非裔美国人的低甲基化基因与包括狼疮在内的自身免疫性疾病密切相关。然后我们证实，与欧洲裔美国人血统相比，非裔美国人狼疮患者中的这些基因，如 IL32、CD226、CDKN1A 和 PTPRN2 类似地低甲基化。使用补丁 DNA 甲基化和荧光素酶报告基因构建体，我们发现 IL32 启动子区域的甲基化会降低体外基因表达。重要的是，亚硫酸氢盐 DNA 测序表明，CpG 位点内的顺式作用遗传变异和直接破坏 CpG 位点是 DNA 甲基化中某些种族特异性变异的原因。 CD4+ T 细胞中种族特异性的遗传性表观遗传易感性位点为解释不同人群之间对自身免疫和可能的其他 T 细胞相关疾病的易感性差异提供了线索。本文的在线版本 (doi:10.1186/s13072-015-0037-1) 包含补充材料，可供授权用户使用。
Genetic and epigenetic variability contributes to the susceptibility and pathogenesis of autoimmune diseases. T cells play an important role in several autoimmune conditions, including lupus, which is more common and more severe in people of African descent. To investigate inherent epigenetic differences in T cells between ethnicities, we characterized genome-wide DNA methylation patterns in naïve CD4+ T cells in healthy African-Americans and European-Americans, and then confirmed our findings in lupus patients. Impressive ethnicity-specific clustering of DNA methylation profiling in naïve CD4+ T cells was revealed. Hypomethylated loci in healthy African-Americans were significantly enriched in pro-apoptotic and pro-inflammatory genes. We also found hypomethylated genes in African-Americans to be disproportionately related to autoimmune diseases including lupus. We then confirmed that these genes, such as IL32, CD226, CDKN1A, and PTPRN2 were similarly hypomethylated in lupus patients of African-American compared to European-American descent. Using patch DNA methylation and luciferase reporter constructs, we showed that methylation of the IL32 promoter region reduces gene expression in vitro. Importantly, bisulfite DNA sequencing demonstrated that cis-acting genetic variants within and directly disrupting CpG sites account for some ethnicity-specific variability in DNA methylation. Ethnicity-specific inherited epigenetic susceptibility loci in CD4+ T cells provide clues to explain differences in the susceptibility to autoimmunity and possibly other T cell-related diseases between populations. The online version of this article (doi:10.1186/s13072-015-0037-1) contains supplementary material, which is available to authorized users.