Arttu Jolma, Aldo Hernández-Corchado, Ally Yang, Ali Fathi, Kaitlin U. Laverty, Alexander Brechalov, Rozita Razavi, Mihai Albu, Hong Zheng, Philipp Bucher, Bart Deplancke, Oriol Fornés, Jan Grau, Ivo Grosse, Fedor A. Kolpakov, Vsevolod J. Makeev, Marjan Barazandeh, Zhenfeng Deng, Chun Hu, Samuel A. Lambert, Zain M. Patel, Sara E. Pour, Mikhail Salnikov, Isaac Yellan, G. A. Meshcheryakov, Giovanna Ambrosini, Antoni J. Gralak, Sachi Inukai, Judith F. Kribelbauer, Marie-Luise Plescher, Semyon Kolmykov, Ivan Yevshin, Nikita Gryzunov, Ivan Kozin, Mikhail Nikonov, Vladimir Nozdrin, Arsenii Zinkevich, Kateřina Faltejsková, Pavel Kravchenko, Sergey Abramov, Alexandr Boytsov, Vasilii Kamenets, Dmitry Penzar, Anton Vlasov, Ilya E. Vorontsov, Quaid Morris, Xiaoting Chen, Matthew T. Weirauch, Ivan V. Kulakovskiy, Hamed S. Najafabadi, Timothy Hughes
Abstract There is ongoing debate regarding the degree to which transcription factors (TFs) independently specify genomic binding: TF binding motifs are typically short and degenerate, yielding many more binding site predictions than observed in cells. Here we present genomic high-throughput SELEX (GHT-SELEX)—a scalable method that surveys intrinsic binding of purified TFs to the fragmented, naked and unmodified genome. GHT-SELEX peaks for 179 diverse human TFs display surprisingly high overlap with chromatin immunoprecipitation sequencing peaks for the same TF. Comparable overlap can be obtained from motifs using appropriate analytical approaches. For C2H2 zinc finger (zf) proteins—the largest class of human TFs—GHT-SELEX shows that modular, alternative engagement of C2H2-zf domains is the norm, enabling several types of distinct target sites, and frequently involving internal duplication and divergence within the C2H2-zf array. Altogether, it is common for TFs to delineate a large fraction of in vivo genomic binding sites independently of other cellular factors.