风险位11q13.5的远端增强剂促进Treg细胞抑制大肠炎
Rabab Nasrallah1, Charlotte J Imianowski2,3, Lara Bossini-Castillo4
1Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, UK.
Nature
|June 6, 2020
概括
非编码增强剂的遗传变异会影响自身免疫和过敏性疾病. 在CD4+调节T细胞中的特定增强剂控制Lrrc32 (GARP) 表达,这对于抑制大肠炎至关重要,也是潜在的治疗点.
科学领域:
- 遗传学
- 免疫学
- 分子生物学
背景情况:
- 非编码调节元件 (增强剂) 的遗传变异与复杂的自身免疫和过敏性疾病有关.
- 由于研究其细胞类型特异性和体外建模的挑战,许多与疾病相关的增强剂的功能仍然未知.
研究的目的:
- 在11q13.5自身免疫和过敏疾病风险位点研究特定增强剂的功能.
- 阐明这种增强剂调节免疫细胞基因表达的机制及其在疾病病理学中的作用.
主要方法:
- 在小鼠中使用共享合成的增强剂同类物的功能丧失分析.
- 在CD4+调控T (Treg) 细胞中研究增强剂功能.
- 利用CRISPR激活 (CRISPRa) 来对人类细胞中的11q13.5位点进行功能精细映射.
主要成果:
- 在CD4+调节T细胞中确定了11q13.5的远端增强剂,这对于抑制大肠炎至关重要.
- 这种增强剂通过招募STAT5和NF-κB来调节Lrrc32的信号驱动表达.
- 缺乏增强剂的小鼠显示Treg细胞中的GARP表达减少和肠炎抑制受损;人类增强剂变体与减少的GARP表达相关.
结论:
- 11q13. 5增强剂对Treg细胞中的GARP表达和免疫平衡至关重要,为自身免疫和过敏性疾病提供了机制性联系.
- GARP成为与此位点相关的免疫媒介疾病的潜在治疗点.
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