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Human genome-wide measurement of drug-responsive regulatory activity.

Publication ,  Journal Article
Johnson, GD; Barrera, A; McDowell, IC; D'Ippolito, AM; Majoros, WH; Vockley, CM; Wang, X; Allen, AS; Reddy, TE
Published in: Nat Commun
December 21, 2018

Environmental stimuli commonly act via changes in gene regulation. Human-genome-scale assays to measure such responses are indirect or require knowledge of the transcription factors (TFs) involved. Here, we present the use of human genome-wide high-throughput reporter assays to measure environmentally-responsive regulatory element activity. We focus on responses to glucocorticoids (GCs), an important class of pharmaceuticals and a paradigmatic genomic response model. We assay GC-responsive regulatory activity across >108 unique DNA fragments, covering the human genome at >50×. Those assays directly detected thousands of GC-responsive regulatory elements genome-wide. We then validate those findings with measurements of transcription factor occupancy, histone modifications, chromatin accessibility, and gene expression. We also detect allele-specific environmental responses. Notably, the assays did not require knowledge of GC response mechanisms. Thus, this technology can be used to agnostically quantify genomic responses for which the underlying mechanism remains unknown.

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Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

December 21, 2018

Volume

9

Issue

1

Start / End Page

5317

Location

England

Related Subject Headings

  • Regulatory Elements, Transcriptional
  • Humans
  • High-Throughput Screening Assays
  • Glucocorticoids
  • Genome, Human
  • Gene-Environment Interaction
  • Gene Expression Regulation
 

Citation

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Johnson, G. D., Barrera, A., McDowell, I. C., D’Ippolito, A. M., Majoros, W. H., Vockley, C. M., … Reddy, T. E. (2018). Human genome-wide measurement of drug-responsive regulatory activity. Nat Commun, 9(1), 5317. https://doi.org/10.1038/s41467-018-07607-x
Johnson, Graham D., Alejandro Barrera, Ian C. McDowell, Anthony M. D’Ippolito, William H. Majoros, Christopher M. Vockley, Xingyan Wang, Andrew S. Allen, and Timothy E. Reddy. “Human genome-wide measurement of drug-responsive regulatory activity.Nat Commun 9, no. 1 (December 21, 2018): 5317. https://doi.org/10.1038/s41467-018-07607-x.
Johnson GD, Barrera A, McDowell IC, D’Ippolito AM, Majoros WH, Vockley CM, et al. Human genome-wide measurement of drug-responsive regulatory activity. Nat Commun. 2018 Dec 21;9(1):5317.
Johnson, Graham D., et al. “Human genome-wide measurement of drug-responsive regulatory activity.Nat Commun, vol. 9, no. 1, Dec. 2018, p. 5317. Pubmed, doi:10.1038/s41467-018-07607-x.
Johnson GD, Barrera A, McDowell IC, D’Ippolito AM, Majoros WH, Vockley CM, Wang X, Allen AS, Reddy TE. Human genome-wide measurement of drug-responsive regulatory activity. Nat Commun. 2018 Dec 21;9(1):5317.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

December 21, 2018

Volume

9

Issue

1

Start / End Page

5317

Location

England

Related Subject Headings

  • Regulatory Elements, Transcriptional
  • Humans
  • High-Throughput Screening Assays
  • Glucocorticoids
  • Genome, Human
  • Gene-Environment Interaction
  • Gene Expression Regulation