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Updated: Sep 9, 2025

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多重重叠的结合点决定了转录因子占用率

Shubham Khetan¹, Brent S Carroll¹, Martha L Bulyk^2,3

¹Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

|September 3, 2025

概括

我们开发了PADIT-seq以发现新的,低亲和度的转录因子 (TF) 的DNA结合点. 这揭示了重叠的结合点如何集体控制基因表达,并影响人类的特征和疾病.

科学领域:

基因组学
分子生物学
生物信息学

背景情况:

转录因子 (TF) 通过特定序列的DNA相互作用来调节基因表达.
现有的高吞吐量方法难以识别低亲缘关系的TF结合位点,这对基因调节至关重要.
低 afinity 位点越来越多地被认可为它们在精确的时空基因表达控制中的作用.

研究的目的:

开发一种用于全面测定TF DNA结合偏好的新方法.
确定以前未被检测到的低亲缘关系TF结合点.
提出TF结合的新模型及其在基因调节和疾病中的作用.

主要方法:

通过体外转录和RNA测序 (PADIT-seq) 来开发蛋白与DNA的亲和力.
在所有十个基对DNA序列中对六个TF的结合偏好的综合测定.
分析TF结合点重叠及其对基因组占用率的影响.

主要成果:

PADIT-seq成功检测了数百个新的,低亲和度的TFsDNA结合点.
在高亲和度位点旁边的核酸会形成重叠的低亲和度位点,在体内调节TF结合.
一个基于多重重叠站点的TF绑定模型被提出.

结论:

TF结合是由多个重叠结合位点的集体效应决定的,而不仅仅是单个高亲和度位点.
重叠绑定模型解释了TF的竞争和相似TF的区别绑定场所使用情况.
该模型重新定义了非编码变体的影响,展示了它们如何改变多个部位以影响基因表达,人类特征和疾病.

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