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ChIP-exo signal associated with DNA-binding motifs provides insight into the genomic binding of the glucocorticoid receptor and cooperating transcription factors

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Starick,  Stephan R.
Mechanisms of Transcriptional Regulation (Sebastiaan H. Meijsing), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

Ibn-Salem,  Jonas
Mechanisms of Transcriptional Regulation (Sebastiaan H. Meijsing), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Jurk,  Marcel
Mechanisms of Transcriptional Regulation (Sebastiaan H. Meijsing), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Love,  Michael I.
IMPRS for Computational Biology and Scientific Computing - IMPRS-CBSC (Kirsten Kelleher), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Chung,  Ho-Ryun
Computational Epigenetics (Ho-Ryun Chung), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Vingron,  Martin
Gene regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Meijsing,  Sebastian H.
Mechanisms of Transcriptional Regulation (Sebastiaan H. Meijsing), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Starick, S. R., Ibn-Salem, J., Jurk, M., Hernandez, C., Love, M. I., Chung, H.-R., et al. (2015). ChIP-exo signal associated with DNA-binding motifs provides insight into the genomic binding of the glucocorticoid receptor and cooperating transcription factors. Genome Res, 25(6), 825-835. doi:10.1101/gr.185157.114.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002A-35A9-9
Abstract
The classical DNA recognition sequence of the glucocorticoid receptor (GR) appears to be present at only a fraction of bound genomic regions. To identify sequences responsible for recruitment of this transcription factor (TF) to individual loci, we turned to the high-resolution ChIP-exo approach. We exploited this signal by determining footprint profiles of TF binding at single-base-pair resolution using ExoProfiler, a computational pipeline based on DNA binding motifs. When applied to our GR and the few available public ChIP-exo data sets, we find that ChIP-exo footprints are protein- and recognition sequence-specific signatures of genomic TF association. Furthermore, we show that ChIP-exo captures information about TFs other than the one directly targeted by the antibody in the ChIP procedure. Consequently, the shape of the ChIP-exo footprint can be used to discriminate between direct and indirect (tethering to other DNA-bound proteins) DNA association of GR. Together, our findings indicate that the absence of classical recognition sequences can be explained by direct GR binding to a broader spectrum of sequences than previously known, either as a homodimer or as a heterodimer binding together with a member of the ETS or TEAD families of TFs, or alternatively by indirect recruitment via FOX or STAT proteins. ChIP-exo footprints also bring structural insights and locate DNA:protein cross-link points that are compatible with crystal structures of the studied TFs. Overall, our generically applicable footprint-based approach uncovers new structural and functional insights into the diverse ways of genomic cooperation and association of TFs.