动态染色体结构识别了IL2的新型自身免疫相关增强剂和调节CD4+T细胞激活的新型基因
Matthew C Pahl1,2, Prabhat Sharma1,3, Rajan M Thomas1,3
1Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, United States.
eLife
|September 20, 2024
概括
与自身免疫性疾病相关的遗传变异会影响T细胞调节. 这项研究将这些变异映射到调控元素中,揭示了新的基因和机制,驱动T细胞激活和疾病风险.
科学领域:
- 免疫学 免疫学 免疫学
- 遗传学 是一个遗传学.
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
背景情况:
- 全基因组关联研究 (GWAS) 已经确定了许多自身免疫性疾病的遗传风险因素,主要是在非编码DNA中.
- 这些非编码变体可能通过改变 cis调节元件 (cRE) 的功能来影响自身免疫性疾病.
- 了解免疫细胞激活期间cRE的动态表观遗传活性对于破译自身免疫性疾病机制至关重要.
研究的目的:
- 在激活过程中将自身免疫疾病风险变异映射到 CD4+ T 细胞中活性 cRE.
- 描述基因表达,染色质可访问性和促进体-cRE相互作用之间的动态关系.
- 识别和功能验证涉及T细胞激活和自身免疫性疾病的新基因和调节元件.
主要方法:
- 将GWAS数据与激活的人类CD4+T细胞的表观遗传特征 (RNA-seq, ATAC-seq, Hi-C) 进行整合.
- 鉴定与疾病相关变异和动态调节的cRE相关的蛋白质编码基因.
- 在人类和小鼠模型中对候选增强剂和基因进行功能验证,包括药理学研究.
主要成果:
- 约有1200个蛋白质编码基因通过可访问的cRE与423个GWAS信号联系在一起,超过三分之一的基因在T细胞激活期间动态调节.
- 确定了一种对激活诱导IL2表达至关重要的新型保护增强剂,并表明受自身免疫变异的影响.
- 在这项研究中涉及的基因被丰富为CD4+T细胞功能和免疫的先天性错误,有八种新的T细胞激活调节器得到验证.
结论:
- 自免疫风险变体可以改变cRE的功能,影响对CD4+T细胞激活和增殖至关重要的基因表达程序.
- 这种方法可以识别出有助于自身免疫性疾病发病的新基因和调节元件.
- 这些发现为了解遗传变异如何影响免疫细胞功能和疾病易感性提供了一个框架.
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