...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Clinical epigenetics. >Increased Set1 binding at the promoter induces aberrant epigenetic alterations and up-regulates cyclic adenosine 5'-monophosphate response element modulator alpha in systemic lupus erythematosus
【24h】

Increased Set1 binding at the promoter induces aberrant epigenetic alterations and up-regulates cyclic adenosine 5'-monophosphate response element modulator alpha in systemic lupus erythematosus

机译：Set1在启动子上的结合增加诱导异常的表观遗传学改变，并上调系统性红斑狼疮中的环状腺苷5'-单磷酸反应元件调节剂α。

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

class="Heading">Background id="Par1" class="Para">Up-regulated cyclic adenosine 5'-monophosphate response element modulator ?± (CREM?±) which can inhibit IL-2 and induce IL-17A in T cells plays a critical role in the pathogenesis of systemic lupus erythematosus (SLE). This research aimed to investigate the mechanisms regulating CREM?± expression in SLE. class="Heading">Results id="Par2" class="Para">From the chromatin immunoprecipitation (ChIP) microarray data, we found a sharply increased H3 lysine 4 trimethylation (H3K4me3) amount at the CREM?± promoter in SLE CD4+ T cells compared to controls. Then, by ChIP and real-time PCR, we confirmed this result. Moreover, H3K4me3 amount at the promoter was positively correlated with CREM?± mRNA level in SLE CD4+ T cells. In addition, a striking increase was observed in SET domain containing 1 (Set1) enrichment, but no marked change in mixed-lineage leukemia 1 (MLL1) enrichment at the CREM?± promoter in SLE CD4+ T cells. We also proved Set1 enrichment was positively correlated with both H3K4me3 amount at the CREM?± promoter and CREM?± mRNA level in SLE CD4+ T cells. Knocking down Set1 with siRNA in SLE CD4+ T cells decreased Set1 and H3K4me3 enrichments, and elevated the levels of DNMT3a and DNA methylation, while the amounts of H3 acetylation (H3ac) and H4 acetylation (H4ac) didna€?t alter greatly at the CREM?± promoter. All these changes inhibited the expression of CREM?±, then augmented IL-2 and down-modulated IL-17A productions. Subsequently, we observed that DNA methyltransferase (DNMT) 3a enrichment at the CREM?± promoter was down-regulated significantly in SLE CD4+ T cells, and H3K4me3 amount was negatively correlated with both DNA methylation level and DNMT3a enrichment at the CREM?± promoter in SLE CD4+ T cells. class="Heading">Conclusions id="Par3" class="Para">In SLE CD4+ T cells, increased Set1 enrichment up-regulates H3K4me3 amount at the CREM?± promoter, which antagonizes DNMT3a and suppresses DNA methylation within this region. All these factors induce CREM?± overexpression, consequently result in IL-2 under-expression and IL-17A overproduction, and contribute to SLE at last. Our findings provide a novel approach in SLE treatment.
机译：class =“ Heading”>背景 id =“ Par1” class =“ Para”>上调的环状腺苷5'-单磷酸反应元件调节剂α±（CREMα±），可抑制IL- 2，并在T细胞中诱导IL-17A在系统性红斑狼疮（SLE）的发病机理中起关键作用。这项研究旨在研究调节SLE中CREM？±表达的机制。 class =“ Heading”>结果 id =“ Par2” class =“ Para”>来自染色质免疫沉淀（ ChIP）芯片数据，我们发现与对照组相比，SLE CD4 + T细胞中CREM？±启动子处的H3赖氨酸4三甲基化（H3K4me3）量急剧增加。然后，通过ChIP和实时PCR证实了这一结果。此外，启动子处的H3K4me3量与SLE CD4 + T细胞中的CREMα±mRNA水平呈正相关。另外，在含有1（Set1）富集的SET结构域中观察到惊人的增加，但在SLE CD4 + T细胞中CREMα±启动子上的混合谱系白血病1（MLL1）富集没有明显变化。我们还证明了Set1富集与SLE CD4 + T细胞中CREMα±启动子的H3K4me3量和CREMα±mRNA水平呈正相关。在SLE CD4 + T细胞中用siRNA敲除Set1会降低Set1和H3K4me3的富集，并增加DNMT3a和DNA甲基化的水平，而CREM处H3乙酰化（H3ac）和H4乙酰化（H4ac）的量却没有太大变化。 α±启动子。所有这些变化抑制了CREMα±的表达，然后增加了IL-2和下调了IL-17A的产生。随后，我们观察到SLE CD4 + T细胞中CREMα±启动子的DNA甲基转移酶（DNMT）3a富集显着下调，并且H3K4me3量与CREMα±启动子中的DNA甲基化水平和DNMT3a富集呈负相关。 SLE CD4 + T细胞。 class =“ Heading”>结论 id =“ Par3” class =“ Para”>在SLE CD4 + T细胞中，增加的Set1富集上调H3K4me3的含量CREMα±启动子，其拮抗DNMT3a并抑制该区域内的DNA甲基化。所有这些因素都会导致CREMα±过度表达，从而导致IL-2的过度表达和IL-17A的过度产生，并最终导致SLE。我们的发现为SLE治疗提供了一种新颖的方法。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号