Genome-wide DNA methylation study suggests epigenetic accessibility and transcriptional poising of interferon-regulated genes in naïve CD4+ T cells from lupus patients.
Genome-wide DNA methylation study suggests epigenetic accessibility and transcriptional poising of interferon-regulated genes in naïve CD4+ T cells from lupus patients.
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DOI：
10.1016/j.jaut.2013.04.003
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发表时间：
2013-06
影响因子：
12.8
通讯作者：
Sawalha AH
中科院分区：
文献类型：
--
作者：
Coit P;Jeffries M;Altorok N;Dozmorov MG;Koelsch KA;Wren JD;Merrill JT;McCune WJ;Sawalha AH
系统性红斑狼疮是一种以多系统受累和自身抗体产生为特征的自身免疫性疾病。T细胞DNA甲基化异常和I型干扰素在狼疮的发病机制中起重要作用。我们在两组独立的狼疮患者和匹配的健康对照中进行了全基因组DNA甲基化研究，以表征狼疮中幼稚CD4+ T细胞的DNA甲基化组。对基因组中超过485，000个甲基化位点的DNA甲基化进行了定量，并确定了狼疮患者和对照组之间的差异甲基化位点，然后独立复制。还对相同细胞进行基因表达分析，以研究观察到的DNA甲基化变化与mRNA表达水平之间的关系。我们在47个基因中确定并复制了患者和对照组之间的86个差异甲基化CG位点，其中大多数是低甲基化的。我们在狼疮患者的初始T细胞中观察到干扰素调节基因的显著低甲基化，包括IFIT1，IFIT3，MX1，STAT1，IFI44L，USP 18，TRIM 22和BST 2，表明这些遗传基因座中的表观遗传转录可及性。事实上，大多数低甲基化基因（35个低甲基化基因中的21个）受I型干扰素调控。干扰素调节基因的低甲基化与狼疮活动性无关。基因表达分析显示，这些基因在狼疮患者的总CD4+ T细胞中过表达，但在初始CD4+ T细胞中没有过表达。我们的数据表明，干扰素调节的基因在狼疮幼稚的CD4+ T细胞的表观遗传“平衡”，认为一个新的致病性的影响，异常的T细胞DNA甲基化在狼疮，并提出了一种机制，I型干扰素高反应性狼疮T细胞。
Systemic lupus erythematosus is an autoimmune disease characterized by multi-system involvement and autoantibody production. Abnormal T cell DNA methylation and type-I interferon play an important role in the pathogenesis of lupus. We performed a genome-wide DNA methylation study in two independent sets of lupus patients and matched healthy controls to characterize the DNA methylome in naïve CD4+ T cells in lupus. DNA methylation was quantified for over 485,000 methylation sites across the genome, and differentially methylated sites between lupus patients and controls were identified and then independently replicated. Gene expression analysis was also performed from the same cells to investigate the relationship between the DNA methylation changes observed and mRNA expression levels. We identified and replicated 86 differentially methylated CG sites between patients and controls in 47 genes, with the majority being hypomethylated. We observed significant hypomethylation in interferon-regulated genes in naïve T cells from lupus patients, including IFIT1, IFIT3, MX1, STAT1, IFI44L, USP18, TRIM22 and BST2, suggesting epigenetic transcriptional accessibility in these genetic loci. Indeed, the majority of the hypomethylated genes (21 out of 35 hypomethylated genes) are regulated by type I interferon. The hypomethylation in interferon-regulated genes was not related to lupus disease activity. Gene expression analysis showed overexpression of these genes in total but not naïve CD4+ T cells from lupus patients. Our data suggest epigenetic “poising” of interferon-regulated genes in lupus naïve CD4+ T cells, argue for a novel pathogenic implication for abnormal T cell DNA methylation in lupus, and suggest a mechanism for type-I interferon hyper-responsiveness in lupus T cells.
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影响因子：
--
作者：
Webb, Ryan;Merrill, Joan T.;Kelly, Jennifer A.;Sestak, Andrea;Kaufman, Kenneth M.;Langefeld, Carl D.;Ziegler, Julie;Kimberly, Robert P.;Edberg, Jeffrey C.;Ramsey-Goldman, Rosalind;Petri, Michelle;Reveille, John D.;Alarcon, Graciela S.;Vila, Luis M.;Alarcon-Riquelme, Marta E.;James, Judith A.;Gilkeson, Gary S.;Jacob, Chaim O.;Moser, Kathy L.;Gaffney, Patrick M.;Vyse, Timothy J.;Nath, Swapan K.;Lipsky, Peter;Harley, John B.;Sawalha, Amr H.
通讯作者：
Sawalha, Amr H.
DOI：
10.4049/jimmunol.182.1.34
发表时间：
2009-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kariuki SN;Kirou KA;MacDermott EJ;Barillas-Arias L;Crow MK;Niewold TB
通讯作者：
Niewold TB
影响因子：
30.8
作者：
Jones, PL;Veenstra, GJC;Wolffe, AP
通讯作者：
Wolffe, AP
影响因子：
3.3
作者：
Kuhl BD;Sloan RD;Donahue DA;Bar-Magen T;Liang C;Wainberg MA
通讯作者：
Wainberg MA
MECP2/IRAK1 狼疮风险单倍型在人类 T 细胞和人类 MECP2 转基因小鼠中的功能特征。
影响因子：
12.8
作者：
Koelsch KA;Webb R;Jeffries M;Dozmorov MG;Frank MB;Guthridge JM;James JA;Wren JD;Sawalha AH
通讯作者：
Sawalha AH