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通过多增强器枢纽对Ets1剂量的定量控制促进了Th1细胞的分化,并防止过敏性炎症

Aditi Chandra¹, Sora Yoon¹, Michaël F Michieletto²

¹Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

|June 1, 2023

概括

多增强器集线器通过控制Ets1基因剂量来调节T辅助1细胞的分化. 这些中心的序列变化与过敏性疾病有关,影响T细胞反应.

科学领域:

基因组学就是基因组学.
免疫学免疫学免疫学
发展生物学发展生物学

背景情况:

多增强器枢纽是增强器的空间集群,对开发计划至关重要.
这些3D结构在T细胞生物学中的功能意义仍然不完全理解.
非编码的监管元素是与人类疾病相关的序列变异的热点.

研究的目的:

研究多增强器枢纽在T细胞生物学中的作用.
阐明在Ets1位点的特定多增强器枢纽影响T细胞分化和疾病易感性的机制.
了解非编码元素的序列变异对过敏反应的影响.

主要方法:

数学建模用于识别多增强器集线器.
在小鼠中进行基因删除研究以评估功能相关性.
分析T助手1 (Th1) 细胞分化,T细胞介导的大肠炎和过敏反应.
研究涉及Ets1剂量,CTCF招募和基因组拓学的分子机制.

主要成果:

在Ets1位点确定了一个高度连接的多增强器枢纽,其中含有易于与过敏相关的序列变异的调节元件.
这种元素的删除并没有影响T细胞的发育,但影响了CD4+T助手1 (Th1) 的分化.
缺乏该元素的小鼠受到Th1-介导性结肠炎的保护,但显示出高度的过敏反应.
发现该中心控制了Ets1剂量,这对于CTCF招募和Th1特定基因组拓学至关重要.

结论:

多增强剂枢纽对于通过定量控制 Ets1 基因剂量来实现 Th1 差异化至关重要.
鉴定的枢纽通过精确的基因剂量控制来调节细胞对诱导线索的反应.
在Ets1位点的非编码元素的序列变化通过破坏这种调节机制,有助于对过敏疾病的易感性.

关键词:

3D基因组组织 3D基因组组织 CD4 T助手差异化CD4 T助手差异化在ETS1中,ETS1是ETS1.过敏性炎症是一种过敏性炎症.过敏是一种过敏.喘喘是一种大肠炎是一种大肠炎.剂量控制剂量控制多增强器集线器集线器转录因子的转录因子

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