DNA methylation in Cosmc promoter region and aberrantly glycosylated IgA1 associated with pediatric IgA nephropathy.
DNA methylation in Cosmc promoter region and aberrantly glycosylated IgA1 associated with pediatric IgA nephropathy.
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DOI：
10.1371/journal.pone.0112305
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Shen Y
中科院分区：
文献类型：
--
作者：
Sun Q;Zhang J;Zhou N;Liu X;Shen Y
IgA 肾病（IgAN）是导致终末期肾衰竭的最常见肾小球疾病之一。异常糖基化 IgA1 的升高是其一个关键特征。已知 core1ß1, 3 半乳糖基转移酶 (Cosmc) 的特定分子伴侣的表达在 IgAN 中降低。我们的目的是研究 Cosmc 基因启动子区 CpG 岛的甲基化是否可能作为 IgA 肾病儿童淋巴细胞中 Cosmc 下调以及相关的异常糖基化 IgA1 分泌增加的可能机制。包括三组：IgAN 儿童（n = 26）、其他肾脏疾病（n = 11）和健康儿童（n = 13）。分离并培养 B 淋巴细胞，用 IL-4 或 5-Aza-2’-脱氧胞苷 (AZA) 处理或不处理。三个儿童群体淋巴细胞中Cosmc启动子区DNA甲基化水平无显着差异（P=0.113），但IL-4（P<0.0001）或AZA（P<0.0001）后IgAN淋巴细胞与其他两个儿童群体淋巴细胞之间存在显着差异。与其他两组相比，IgAN 淋巴细胞中的 Cosmc mRNA 表达较低（P<0.0001）。 IgAN组异常糖基化IgA1水平显着高于其他组（P<0.0001）。 IL-4处理后，IgAN淋巴细胞中Cosmc DNA甲基化和异常糖基化IgA1水平显着高于其他两组（P<0.0001），Cosmc mRNA含量下降更显着（P<0.0001）。 AZA治疗后，IgAN淋巴细胞水平降低，但仍显着高于其他两组（P<0.0001），而IgAN淋巴细胞中Cosmc mRNA含量较其他两组显着升高（P<0.0001）。 IL-4 或 AZA 对 DNA 甲基化的改变在 IgAN 淋巴细胞中与 Cosmc mRNA 表达的改变以及异常糖基化 IgA1 的水平特别相关 (r = -0.948, r = 0. 707)。我们的结果表明，Cosmc 启动子区域的高甲基化可能是 IgAN 淋巴细胞中 Cosmc mRNA 表达减少以及异常糖基化 IgA1 相关增加的关键机制。
IgA nephropathy (IgAN) is one of the most common glomerular diseases leading to end-stage renal failure. Elevation of aberrantly glycosylated IgA1 is a key feature of it. The expression of the specific molecular chaperone of core1ß1, 3galactosyl transferase (Cosmc) is known to be reduced in IgAN. We aimed to investigate whether the methylation of CpG islands of Cosmc gene promoter region could act as a possible mechanism responsible for down-regulation of Cosmc and related higher secretion of aberrantly glycosylated IgA1in lymphocytes from children with IgA nephropathy. Three groups were included: IgAN children (n = 26), other renal diseases (n = 11) and healthy children (n = 13). B-lymphocytes were isolated and cultured, treated or not with IL-4 or 5-Aza-2’-deoxycytidine (AZA). The levels of DNA methylation of Cosmc promotor region were not significantly different between the lymphocytes of the three children populations (P = 0.113), but there were significant differences between IgAN lymphocytes and lymphocytes of the other two children populations after IL-4 (P<0.0001) or AZA (P<0.0001). Cosmc mRNA expression was low in IgAN lymphocytes compared to the other two groups (P<0.0001). The level of aberrantly glycosylated IgA1 was markedly higher in IgAN group compared to the other groups (P<0.0001). After treatment with IL-4, the levels of Cosmc DNA methylation and aberrantly glycosylated IgA1 in IgAN lymphocytes were remarkably higher than the other two groups (P<0.0001) with more markedly decreased Cosmc mRNA content (P<0.0001). After treatment with AZA, the levels in IgAN lymphocytes were decreased, but was still remarkably higher than the other two groups (P<0.0001), while Cosmc mRNA content in IgAN lymphocytes were more markedly increased than the other two groups (P<0.0001). The alteration of DNA methylation by IL-4 or AZA specifically correlates in IgAN lymphocytes with alterations in Cosmc mRNA expression and with the level of aberrantly glycosylated IgA1 (r = −0.948, r = 0. 707). Our results suggested that hypermethylation of Cosmc promoter region could be a key mechanism for the reduction of Cosmc mRNA expression in IgAN lymphocytes with associated increase in aberrantly glycosylated IgA1.
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影响因子：
3.7
作者：
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