Functional characterization of the MECP2/IRAK1 lupus risk haplotype in human T cells and a human MECP2 transgenic mouse.
Functional characterization of the MECP2/IRAK1 lupus risk haplotype in human T cells and a human MECP2 transgenic mouse.
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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。
DOI：
10.1016/j.jaut.2012.12.012
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发表时间：
2013-03
影响因子：
12.8
通讯作者：
Sawalha AH
中科院分区：
文献类型：
--
作者：
Koelsch KA;Webb R;Jeffries M;Dozmorov MG;Frank MB;Guthridge JM;James JA;Wren JD;Sawalha AH
染色体Xq 28上MECP 2/IRAK 1的遗传多态性是狼疮的一个确认和复制的易感位点。该位点的高度连锁不平衡表明MECP 2和IRAK 1都是该病的候选基因。狼疮T细胞中的DNA甲基化变化在狼疮的发病机制中起着核心作用，MeCp-2（由MECP 2编码）是基因表达的主要调节因子，也已知在DNA合成期间招募DNA甲基转移酶1（DNMT 1）。使用来自具有狼疮风险或狼疮保护性单倍型的正常个体的人T细胞在MECP 2/IRAK 1中，我们证明了在该位点的多态性增加了在刺激的但不是未刺激的T细胞中的MECP 2同种型2 mRNA表达。通过评估整个基因组中超过485，000个甲基化位点的DNA甲基化水平，我们进一步证明了该基因座中的狼疮风险变体与显着的DNA甲基化变化相关，包括HLA-DR和HLA-DQ基因座，以及干扰素相关基因，如IFI 6，IRF 6和BST 2。此外，使用人MECP 2转基因小鼠，我们表明MECP 2的过表达改变了刺激的T细胞中的基因表达。这包括Eif 2c 2的过表达，Eif 2c 2调节多种microRNA（如miR-21）的表达，以及组蛋白去甲基化酶Jhdm 1d。此外，我们表明，MECP 2转基因小鼠产生抗核抗体。我们的数据表明，MECP 2/IRAK 1基因座中的狼疮相关变体有可能影响所有3种表观遗传机制：DNA甲基化，microRNA表达和组蛋白修饰。重要的是，这些数据支持这样一种观点，即MECP 2基因内的变异可以改变其他遗传基因座（包括HLA和干扰素调节基因）中的DNA甲基化，从而为狼疮中的遗传-表观遗传相互作用提供证据。
Genetic polymorphism in MECP2/IRAK1 on chromosome Xq28 is a confirmed and replicated susceptibility locus for lupus. High linkage disequilibrium in this locus suggests that both MECP2 and IRAK1 are candidate genes for the disease. DNA methylation changes in lupus T cells play a central role in the pathogenesis of lupus, and MeCp-2 (encoded by MECP2) is a master regulator of gene expression and is also known to recruit DNA methyltransferase 1 (DNMT1) during DNA synthesis. Using human T cells from normal individuals with either the lupus risk or the lupus protective haplotype in MECP2/IRAK1, we demonstrate that polymorphism in this locus increases MECP2 isoform 2 mRNA expression in stimulated but not unstimulated T cells. By assessing DNA methylation levels across over 485,000 methylation sites across the entire genome, we further demonstrate that the lupus risk variant in this locus is associated with significant DNA methylation changes, including in the HLA-DR and HLA-DQ loci, as well as interferon-related genes such as IFI6, IRF6, and BST2. Further, using a human MECP2 transgenic mouse, we show that overexpression of MECP2 alters gene expression in stimulated T cells. This includes overexpression of Eif2c2 that regulates the expression of multiple microRNAs (such as miR-21), and the histone demethylase Jhdm1d. In addition, we show that MECP2 transgenic mice develop antinuclear antibodies. Our data suggest that the lupus associated variant in the MECP2/IRAK1 locus has the potential to affect all 3 epigenetic mechanisms: DNA methylation, microRNA expression, and histone modification. Importantly, these data support the notion that variants within the MECP2 gene can alter DNA methylation in other genetic loci including the HLA and interferon-regulated genes, thereby providing evidence for genetic-epigenetic interaction in lupus.
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DOI：
10.1073/pnas.091062498
发表时间：
2001-04-24
影响因子：
11.1
作者：
Tusher, VG;Tibshirani, R;Chu, G
通讯作者：
Chu, G
影响因子：
3.5
作者：
Collins, AL;Levenson, JM;Zoghbi, HY
通讯作者：
Zoghbi, HY
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
影响因子：
4.8
作者：
Kimura, H;Shiota, K
通讯作者：
Shiota, K