Nat Commun:系统性红斑狼疮遗传风险突变体的等位基因增强子活性研究

2021-03-24 xiaozeng MedSci原创

系统性红斑狼疮(SLE)是一种自身免疫性疾病,其可以影响多个器官并最终导致衰弱性炎症反应和死亡。

系统性红斑狼疮(SLE)是一种自身免疫性疾病,其可以影响多个器官并最终导致衰弱性炎症反应和死亡。流行病学研究显示,遗传因素和环境因素在SLE的发生发展中起着至关重要的作用。

目前全基因组关联研究(GWAS)已鉴定出了91个遗传风险基因座,这些基因座在很大程度上以叠加的方式提高SLE的患病风险。该研究旨在探究SLE风险突变体对SLE风险基因座的影响。

在先前的全基因组关联研究中共鉴定了91个风险位点的3073个遗传变异。为了系统地筛选这些突变体的等位基因转录增强子的活性,研究人员构建了一个大规模并行报告基因检测(MPRA)文库,该库包含了12,396个DNA寡核苷酸,其中包括了每个SLE突变体等位基因周围的基因组信息。

大规模并行报告的流程示意图

研究人员在爱泼斯坦-巴尔病毒(EBV)感染的B细胞系GM12878中,发现了482个具有增强子活性的突变体,其中在27个风险基因座处的51个突变体显示出了基因型依赖性(等位基因)增强子活性。

C4A和SYNGR1基因组位点的的相关调控机制

GM12878和Jurkat T细胞系中MPRA结果的比较突出了SLE风险基因座上共享的和独特的等位基因转录调控相关机制。对等位基因突变体及其周围结合的转录因子(TF)深入分析,确定了一类TFs,其DNA的结合基序倾向于被风险突变体直接改变,而另一类TFs则表现为能够与等位基因结合但由于突变的存在无法改变其相关修饰。


总而言之,该研究结果为任何疾病风险基因座的等位基因调控的研究提供了一个蓝图,并为了解SLE的转录调控机制提供了一定的见识。


原始出处:

Lu, X., Chen, X., Forney, C. et al. Global discovery of lupus genetic risk variant allelic enhancer activity. Nat Commun 12, 1611 (12 March 2021).

 

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  5. 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createdName=站在塔尖, createdTime=Thu Mar 25 00:47:13 CST 2021, time=2021-03-25, status=1, ipAttribution=)]
  6. 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  7. 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level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=68144, encryptionId=8a3a6814425, topicName=狼疮)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7a6e2500005, createdName=sunrural_42825357, createdTime=Fri Mar 26 14:05:36 CST 2021, time=2021-03-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1436276, encodeId=90d314362e6e9, content=<a href='/topic/show?id=22f8e71238d' target=_blank style='color:#2F92EE;'>#红斑#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77123, encryptionId=22f8e71238d, topicName=红斑)], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyheQLjPSX3OUs5GmkyBlcCOwTPIeq3why9NGibxxUqYo6hcx8qZLHZFgNPnBK1yzWeOFpyg2OnWOt0/0, createdBy=fa4716, createdName=zhouqu_8, createdTime=Fri Mar 26 14:05:36 CST 2021, time=2021-03-26, status=1, 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createdName=站在塔尖, createdTime=Thu Mar 25 00:47:13 CST 2021, time=2021-03-25, status=1, ipAttribution=)]
    2021-03-26 zhouqu_8
  8. 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    2021-03-25 站在塔尖

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