An expanded codebook of human transcription factor DNA-binding specificity

• 成果类型: Article
• 署名作者: 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.
• 署名单位: University of Toronto; Memorial Sloan Kettering Cancer Center; University of Toronto; Russian Academy of Sciences; Vavilov Institute of General Genetics; Swiss Federal Institutes of Technology Domain; Swiss School of Public Health (SSPH+); Ecole Polytechnique Federale de Lausanne; Swiss Institute of Bioinformatics; University of Southern California; Lomonosov Moscow State University; Russian Academy of Sciences; Russian Academy of Sciences; Institute of Biochemistry & Genetics of Ufa Science Centre of the RAS; University System of Ohio; Cincinnati Children's Hospital Medical Center; University of Cincinnati; University System of Ohio; Cincinnati Children's Hospital Medical Center; University of Cincinnati; Cincinnati Children's Hospital Medical Center; Cincinnati Children's Hospital Medical Center; Cincinnati Children's Hospital Medical Center; University System of Ohio; University of Cincinnati; University of British Columbia; BC Children's Hospital; BC Children's Hospital Research Institute; Martin Luther University Halle Wittenberg; University of Manchester
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-026-10798-9
• 发表日期: 2026-09-03
• 关键词: CPG ISLANDS; motifs; gene; identification; EVOLUTION; DISCOVERY; chromatin; proteins; platform; ELEMENTS

摘要

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.