Genome-wide analysis of ETS-family DNA-binding in vitro and in vivo

• Gong-Hong Wei ^[1] ; Gwenael Badis ^[2] ; Michael F Berger ^[5] ; Teemu Kivioja ^[1] ; Kimmo Palin ^[3] ; Martin Enge ^[6] ; Martin Bonke ^[1] ; Arttu Jolma ^[1] ; Markku Varjosalo ^[1] ; Andrew R Gehrke ^[5] ; Jian Yan ^[1] ; Shaheynoor Talukder ^[2] ; Mikko Turunen ^[1] ; Mikko Taipale ^[1] ; Hendrik G Stunnenberg ^[4] ; Esko Ukkonen ^[3] ; Timothy R Hughes ^[2] ; Martha L Bulyk ^[5] ; Jussi Taipale ^[1]
  1. [1] National Institute for Health and Welfare

     National Institute for Health and Welfare

     Helsinki, Finlandia

     
  2. [2] University of Toronto

     University of Toronto

     Canadá

     
  3. [3] University of Helsinki

     University of Helsinki

     Helsinki, Finlandia

     
  4. [4] Radboud University Nijmegen

     Radboud University Nijmegen

     Países Bajos

     
  5. [5] Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA, USA; Harvard-MIT Division of Health Sciences and Technology (HST), Harvard Medical School, Boston, MA, USA
  6. [6] Department of Biosciences and Medical Nutrition, Karolinska Institutet, Sweden

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 29, Nº. 13, 2010, págs. 2147-2160
• Idioma: inglés
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  • Members of the large ETS family of transcription factors (TFs) have highly similar DNA-binding domains (DBDs)—yet they have diverse functions and activities in physiology and oncogenesis. Some differences in DNA-binding preferences within this family have been described, but they have not been analysed systematically, and their contributions to targeting remain largely uncharacterized. We report here the DNA-binding profiles for all human and mouse ETS factors, which we generated using two different methods: a high-throughput microwell-based TF DNA-binding specificity assay, and protein-binding microarrays (PBMs). Both approaches reveal that the ETS-binding profiles cluster into four distinct classes, and that all ETS factors linked to cancer, ERG, ETV1, ETV4 and FLI1, fall into just one of these classes. We identify amino-acid residues that are critical for the differences in specificity between all the classes, and confirm the specificities in vivo using chromatin immunoprecipitation followed by sequencing (ChIP-seq) for a member of each class. The results indicate that even relatively small differences in in vitro binding specificity of a TF contribute to site selectivity in vivo.