多伦多大学Timothy R. Hughes团队宣布他们提出了人类转录因子DNA结合特异性的扩展码本。2026年8月5日，国际知名学术期刊《自然》发表了这一成果。

在这里，研究组描述了一个系统的工作，以确定332个假定的和特征不明确的人类TF的序列特异性。超过4000个独立实验，包括多种体外和体内分析，产生了超过一半（177个；53%）的TF的基序，其中大多数仅与单一蛋白质相关。这些结果扩展了人类TF编码的序列识别词汇表，增加了大约130个不同的基序。

此外，体外鉴定的结合基序在细胞结合位点强烈富集。总的来说，这些数据揭示了人类基因组中数十种以前未知的、保守的和直接的TF结合位点。这些位点集中在启动子区域，可以预测基因表达。总之，这个新的密码本在解码人类基因组方面迈出了重要的一步。

据介绍，基因表达受转录因子（TFs）调控，转录因子识别特定的DNA序列基序。数百个假定的人类TF，主要通过一个明显的DNA结合结构域来识别，缺乏已知的结合基序。此外，即使对于特征明确的TF，其基序准确反映活细胞结合位点的程度仍存在争议。

附：英文原文

Title: An expanded codebook of human transcription factor DNA-binding specificity

Author: Jolma, Arttu, Laverty, Kaitlin U., Fathi, Ali, Yang, Ally W. H., Yellan, Isaac, Vorontsov, Ilya E., Gralak, Antoni J., Kribelbauer-Swietek, Judith F., Inukai, Sachi, Razavi, Rozita, Albu, Mihai, Brechalov, Alexander, Patel, Zain M., Nozdrin, Vladimir, Meshcheryakov, Georgy, Buyan, Andrey, Kozin, Ivan, Abramov, Sergey, Boytsov, Alexandr, Morris, Quaid, Weirauch, Matthew T., Fornes, Oriol, Makeev, Vsevolod J., Grau, Jan, Grosse, Ivo, Bucher, Philipp, Deplancke, Bart, Kulakovskiy, Ivan V., Hughes, Timothy R.

Issue&Volume: 2026-08-05

Abstract: Gene expression is regulated by transcription factors (TFs), which recognize specific DNA sequence motifs. Several hundred putative human TFs, identified mainly by an apparent DNA-binding domain, lack known binding motifs1. Furthermore, even for well-characterized TFs, it remains controversial the degree to which motifs accurately reflect binding sites in living cells2. Here we describe a systematic effort (‘Codebook’) to determine the sequence specificity of 332 putative and poorly characterized human TFs. More than 4,000 independent experiments, encompassing multiple in vitro and in vivo assays, produced motifs for just over half (177; 53%) of the TFs, of which most are associated with only a single protein. These results extend the vocabulary of sequence recognition encoded by human TFs by around 130 distinct motifs. Moreover, binding motifs identified in vitro are strongly enriched in cellular binding sites. Collectively, the data reveal tens of thousands of previously unknown, conserved and direct TF-binding sites across the human genome. These sites are concentrated in promoter regions and are predictive of gene expression. In summary, this new codebook provides an important step forward in decoding the human genome.

DOI: 10.1038/s41586-026-10798-9

Source: https://www.nature.com/articles/s41586-026-10798-9