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

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.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0002-E4DA-7 Version Permalink: http://hdl.handle.net/21.11116/0000-0002-E4DB-6
Genre: Journal Article

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 Creators:
Schöne, Stefanie1, Author              
Bothe, Anna Melissa1, Author              
Einfeldt, Edda1, Author              
Borschiwer, Marina1, Author              
Benner, Philipp Florian2, Author              
Vingron, Martin2, Author              
Thomas-Chollier, Morgane3, Author              
Meijsing, Sebastiaan H.1, Author              
Affiliations:
1Mechanisms of Transcriptional Regulation (Sebastiaan H. Meijsing), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479641              
2Gene regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479639              
3Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433547              

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 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.

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Language(s): eng - English
 Dates: 2018-10-262018-11-14
 Publication Status: Published online
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 Identifiers: DOI: 10.1371/journal.pgen.1007793
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Title: PLoS Genetics
  Other : PLoS Genet.
Source Genre: Journal
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Publ. Info: San Francisco, CA : Public Library of Science
Pages: 24 Volume / Issue: 14 (11) Sequence Number: e1007793 Start / End Page: - Identifier: ISSN: 1553-7390
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000017180