San Diego, CA, USA. In a significant leap forward in the understanding the development of specific tissue types in mammals, an international team of scientists succeeded in mapping the entire network of DNA-binding transcription factors and their interactions. This global network, indicating which factors can combine to determine cell fate, appears in the journal Cell.

Transcription factors (TFs) are proteins that bind to specific DNA sequences in order to direct which genes should be turned on or off in a tissue. Tissue specificity (e.g. whether embryonic tissue develops into lungs or kidneys or skin) is determined by how and which TFs bind to genes.

Between 2,000 and 3,000 transcription factor proteins are encoded by the human genome, potentially creating more than 4 million potential protein pairings.

It has long been appreciated that different combinations of TFs are active in different tissues. But given the enormous number of TFs and potential pairings, it has been difficult to precisely identify which combinations are functional, according to principal investigator Trey Ideker, PhD, chief of the Division of Genetics at the University of California, San Diego, School of Medicine.

The integrated approach to systematically map all possible combinations of TFs in mammals has generated large data sets in both humans and mice. The complete network contains 762 human and 877 mouse interactions between TFs, indicating TF pairs that can work in combination.

"The availability of this large combinatorial network of transcription factors will provide scientists with many opportunities to study gene regulation, tissue differentiation and evolution in mammals," said Ideker, professor in the Department of Medicine and at UCSD's Jacobs School of Engineering. He added that analysis of the network shows that highly connected TFs are broadly expressed across tissues, and that roughly half of the interactions are conserved between mouse and human.

The research team identified nearly 1,000 different pairs of TF proteins that can be wired together, representing the blueprint of all possible combinations that direct gene expression in mammals. The work may provide researchers with the clues necessary to one day determine how stem cells can be reprogrammed into a particular organ or tissue type.

CitationAn Atlas of Combinatorial Transcriptional Regulation in Mouse and Man. Timothy Ravasi, Harukazu Suzuki, Carlo Vittorio Cannistraci, Shintaro Katayama, Vladimir B. Bajic, Kai Tan, Altuna Akalin, Sebastian Schmeier, Mutsumi Kanamori-Katayama, Nicolas Bertin, Piero Carninci, Carsten O. Daub, Alistair R.R. Forrest, Julian Gough, Sean Grimmond, Jung-Hoon Han, Takehiro Hashimoto, Winston Hide, Oliver Hofmann, Hideya Kawaji, Atsutaka Kubosaki, Timo Lassmann, Erik van Nimwegen, Chihiro Ogawa, Rohan D. Teasdale, Jesper Tegnér, Boris Lenhard, Sarah A. Teichmann, Takahiro Arakawa, Noriko Ninomiya, Kayoko Murakami, Michihira Tagami, Shiro Fukuda, Kengo Imamura, Chikatoshi Kai, Ryoko Ishihara, Yayoi Kitazume, Jun Kawai, David A. Hume, Trey Ideker and Yoshihide Hayashizaki. Cell 2010; 140(5): 744-752. doi:10.1016/j.cell.2010.01.044

Highlights

• An atlas of human and mouse transcription factor interactions

• Quantification of transcription factor expression across human and mouse tissues

• A network of 15 transcription factors predicts tissue type specification

• SMAD3/FLI1 forms a repressor complex that controls monocyte differentiation

Abstract

Combinatorial interactions among transcription factors are critical to directing tissue-specific gene expression. To build a global atlas of these combinations, we have screened for physical interactions among the majority of human and mouse DNA-binding transcription factors (TFs). The complete networks contain 762 human and 877 mouse interactions. Analysis of the networks reveals that highly connected TFs are broadly expressed across tissues, and that roughly half of the measured interactions are conserved between mouse and human. The data highlight the importance of TF combinations for determining cell fate, and they lead to the identification of a SMAD3/FLI1 complex expressed during development of immunity. The availability of large TF combinatorial networks in both human and mouse will provide many opportunities to study gene regulation, tissue differentiation, and mammalian evolution.

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