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Synthetic STARR-seq reveals how DNA shape and sequence modulate transcriptional output and noise

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Schöne,  Stefanie
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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Bothe,  Anna Melissa
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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Einfeldt,  Edda
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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Borschiwer,  Marina
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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Benner,  Philipp Florian
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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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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Thomas-Chollier,  Morgane
Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Meijsing,  Sebastiaan 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

Schöne, S., Bothe, A. M., Einfeldt, E., Borschiwer, M., Benner, P. F., Vingron, M., et al. (2018). Synthetic STARR-seq reveals how DNA shape and sequence modulate transcriptional output and noise. PLoS Genetics, 14(11): e1007793. doi:10.1371/journal.pgen.1007793.


Cite as: http://hdl.handle.net/21.11116/0000-0002-E4DA-7
Abstract
The binding of transcription factors to short recognition sequences plays a pivotal role in controlling the expression of genes. The sequence and shape characteristics of binding sites influence DNA binding specificity and have also been implicated in modulating the activity of transcription factors downstream of binding. To quantitatively assess the transcriptional activity of tens of thousands of designed synthetic sites in parallel, we developed a synthetic version of STARR-seq (synSTARR-seq). We used the approach to systematically analyze how variations in the recognition sequence of the glucocorticoid receptor (GR) affect transcriptional regulation. Our approach resulted in the identification of a novel highly active functional GR binding sequence and revealed that sequence variation both within and flanking GR’s core binding site can modulate GR activity without apparent changes in DNA binding affinity. Notably, we found that the sequence composition of variants with similar activity profiles was highly diverse. In contrast, groups of variants with similar activity profiles showed specific DNA shape characteristics indicating that DNA shape may be a better predictor of activity than DNA sequence. Finally, using single cell experiments with individual enhancer variants, we obtained clues indicating that the architecture of the response element can independently tune expression mean and cell-to cell variability in gene expression (noise). Together, our studies establish synSTARR as a powerful method to systematically study how DNA sequence and shape modulate transcriptional output and noise.