人类甲转录因子中的错误变异揭示了甲DNA双特异性的决定因素
Jessica King1, Stephen S Gisselbrecht1, Julie-Alexia Dias2
1Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
bioRxiv : the preprint server for biology
|June 9, 2025
概括
转录因子 (TFs) 通过结合DNA来控制基因表达. 这项研究发现,叉 (FH) TFs中的特定非DNA接触氨基酸变异决定了它们是否结合一个或多个DNA动机,从而影响基因调节.
科学领域:
- 分子生物学分子生物学
- 遗传学 遗传学 是一个
- 生物化学 生物化学
背景情况:
- 转录因子 (TFs) 通过识别特定的DNA序列来调节基因表达.
- 叉头 (FH) TFs是关键的监管机构,其中大多数具有约束力的FKH或FHL动机,而一些则具有约束力的两个动机.
- 控制这种单特异性与双特异性DNA结合的机制在很大程度上是未知的.
研究的目的:
- 为了研究控制单种与双种DNA结合在分叉 (FH) 转录因子中的分子机制.
- 为了确定特定的氨基酸残留物,负责确定FH TFs的DNA结合特异性.
主要方法:
- 使用蛋白质结合微阵列 (PBMs) 选DNA结合活性.
- 评估了一个包括参考FH蛋白,自然误解变异 (包括临床变异) 和设计突变的综合图书馆.
- 采用通用10-mer数组用于广泛的DNA图案识别分析.
主要成果:
- 确定了与DNA不接触的氨基酸残留物,这些残留物决定了FH TF是否对DNA基因具有单特异性或双特异性.
- 证明了这些残留物的变化显著改变了TF DNA结合能力.
- 突出了这些残留物在控制TF-DNA相互作用的特异性的作用.
结论:
- 非接触DNA的残留物是FH TF DNA结合特异性的关键决定因素.
- 这些残留物中的变异可以影响TF功能,并可能导致人类特征和基因调节网络的进化变化.
- 这一发现为了解TF多样性及其对基因调节的影响提供了机制基础.
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