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Nascent RNA sequencing reveals a dynamic global transcriptional response at genes and enhancers to the natural medicinal compound celastrol

View ORCID ProfileNoah Dukler, Gregory T. Booth, Yi-Fei Huang, Nathaniel Tippens, Charles G. Danko, John T. Lis, View ORCID ProfileAdam Siepel
doi: https://doi.org/10.1101/117689
Noah Dukler
1Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
2Tri-Institutional Training Program in Computational Biology and Medicine, New York, NY 10065, USA
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  • ORCID record for Noah Dukler
Gregory T. Booth
3Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14850, USA
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Yi-Fei Huang
1Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
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Nathaniel Tippens
2Tri-Institutional Training Program in Computational Biology and Medicine, New York, NY 10065, USA
3Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14850, USA
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Charles G. Danko
4Baker Institute for Animal Health, Cornell University, Ithaca, NY 14850, USA
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John T. Lis
3Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14850, USA
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  • For correspondence: jtl10@cshl.edu asiepel@cshl.edu
Adam Siepel
1Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
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  • ORCID record for Adam Siepel
  • For correspondence: jtl10@cshl.edu asiepel@cshl.edu
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Abstract

Most studies of responses to transcriptional stimuli measure changes in cellular mRNA concentrations. By sequencing nascent RNA instead, it is possible to detect changes in transcription in minutes rather than hours, and thereby distinguish primary from secondary responses to regulatory signals. Here, we describe the use of PRO-seq to characterize the immediate transcriptional response in human cells to celastrol, a compound derived from traditional Chinese medicine that has potent anti-inflammatory, tumor-inhibitory and obesity-controlling effects. Our analysis of PRO-seq data for K562 cells reveals dramatic transcriptional effects soon after celastrol treatment at a broad collection of both coding and noncoding transcription units. This transcriptional response occurred in two major waves, one within 10 minutes, and a second 40-60 minutes after treatment. Transcriptional activity was generally repressed by celastrol, but one distinct group of genes, enriched for roles in the heat shock response, displayed strong activation. Using a regression approach, we identified key transcription factors that appear to drive these transcriptional responses, including members of the E2F and RFX families. We also found sequence-based evidence that particular TFs drive the activation of enhancers. We observed increased polymerase pausing at both genes and enhancers, suggesting that pause release may be widely inhibited during the celastrol response. Our study demonstrates that a careful analysis of PRO-seq time course data can disentangle key aspects of a complex transcriptional response, and it provides new insights into the activity of a powerful pharmacological agent.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 16, 2017.
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Nascent RNA sequencing reveals a dynamic global transcriptional response at genes and enhancers to the natural medicinal compound celastrol
Noah Dukler, Gregory T. Booth, Yi-Fei Huang, Nathaniel Tippens, Charles G. Danko, John T. Lis, Adam Siepel
bioRxiv 117689; doi: https://doi.org/10.1101/117689
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Nascent RNA sequencing reveals a dynamic global transcriptional response at genes and enhancers to the natural medicinal compound celastrol
Noah Dukler, Gregory T. Booth, Yi-Fei Huang, Nathaniel Tippens, Charles G. Danko, John T. Lis, Adam Siepel
bioRxiv 117689; doi: https://doi.org/10.1101/117689

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