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

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Johnson, GD; Barrera, A; McDowell, IC; D'Ippolito, AM; Majoros, WH; Vockley, CM; Wang, X; Allen, AS; Reddy, TE

Published Date

  • December 21, 2018

Published In

Volume / Issue

  • 9 / 1

Start / End Page

  • 5317 -

PubMed ID

  • 30575722

Pubmed Central ID

  • 30575722

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-018-07607-x

Language

  • eng

Conference Location

  • England