Arttu Jolma, Kaitlin U. Laverty, Ali Fathi, Ally Yang, Isaac Yellan, Ilya E. Vorontsov, Antoni J. Gralak, Judith F. Kribelbauer, Sachi Inukai, Rozita Razavi, Mihai Albu, Alexander Brechalov, Zain M. Patel, Vladimir Nozdrin, G. A. Meshcheryakov, Andrey Buyan, Ivan Kozin, Sergey Abramov, Alexandr Boytsov, Fedor A. Kolpakov, Vsevolod J. Makeev, Marjan Barazandeh, Zhenfeng Deng, Chun Hu, Samuel A. Lambert, Sara E. Pour, Mikhail Salnikov, Hong Zheng, Giovanna Ambrosini, Judith F. Kribelbauer, Marie-Luise Plescher, Semyon Kolmykov, Ivan Yevshin, Nikita Gryzunov, Mikhail Nikonov, Arsenii Zinkevich, Kateřina Faltejsková, Pavel Kravchenko, Vasilii Kamenets, Dmitry Penzar, Anton Vlasov, Aldo Hernández-Corchado, Hamed S. Najafabadi, Xiaoting Chen, Quaid Morris, Matthew T. Weirauch, Oriol Fornés, Vsevolod J. Makeev, Jan Grau, Ivo Große, Philipp Bücher, Bart Deplancke, Ivan V. Kulakovskiy, Timothy R. Hughes
Systematically determined the sequence specificity of 332 putative and poorly characterized human TFs using multiple in vitro and in vivo assays. Identified motifs for 177 TFs (53%), extending the vocabulary of sequence recognition by around 130 distinct motifs. Revealed tens of thousands of previously unknown, conserved and direct TF-binding sites across the human genome, concentrated in promoter regions and predictive of gene expression.
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 motifs 1 . Furthermore, even for well-characterized TFs, it remains controversial the degree to which motifs accurately reflect binding sites in living cells 2 . 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.