Dukler, N., Booth, G. T., Huang, Y. F., Tippens, N., Waters, C. T., Danko, C. G., Lis, J. T., Siepel, A. (November 2017) Nascent RNA sequencing reveals a dynamic global transcriptional response at genes and enhancers to the natural medicinal compound celastrol. Genome Res, 27 (11). pp. 1816-1829. ISSN 1088-9051
Preview |
PDF (Paper)
Siepel 2017b.pdf - Published Version Download (8MB) | Preview |
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. Celastrol is known to elicit a cellular stress response resembling the response to heat shock, but the transcriptional basis of this response remains unclear. 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 min, and a second 40-60 min 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 transcription factors 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.
| Item Type: | Paper |
|---|---|
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program > Cancer Genetics CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL labs > Siepel lab |
| Depositing User: | Matt Covey |
| Date: | November 2017 |
| Date Deposited: | 25 Oct 2017 19:19 |
| Last Modified: | 24 May 2021 18:12 |
| PMCID: | PMC5668940 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/35573 |
Actions (login required)
 |
Administrator's edit/view item |