Quantitative Measurement and Thermodynamic Modeling of Fused Enhancers Support a Two-Tiered Mechanism for Interpreting Regulatory DNA

Md Abul Hassan Samee, Tara Lydiard-Martin, Kelly M. Biette, Ben J. Vincent, Meghan D. Bragdon, Kelly B. Eckenrode, Zeba Wunderlich, Javier Estrada, Saurabh Sinha, Angela H. DePace

Research output: Contribution to journalArticlepeer-review

Abstract

Computational models of enhancer function generally assume that transcription factors (TFs) exert their regulatory effects independently, modeling an enhancer as a “bag of sites.” These models fail on endogenous loci that harbor multiple enhancers, and a “two-tier” model appears better suited: in each enhancer TFs work independently, and the total expression is a weighted sum of their expression readouts. Here, we test these two opposing views on how cis-regulatory information is integrated. We fused two Drosophila blastoderm enhancers, measured their readouts, and applied the above two models to these data. The two-tier mechanism better fits these readouts, suggesting that these fused enhancers comprise multiple independent modules, despite having sequence characteristics typical of single enhancers. We show that short-range TF-TF interactions are not sufficient to designate such modules, suggesting unknown underlying mechanisms. Our results underscore that mechanisms of how modules are defined and how their outputs are combined remain to be elucidated. Samee et al. identify a gap in our current assumptions of how regulatory sequences control gene expression. It is generally assumed that regulatory sequences act as single modules on transcriptional machinery. Quantitative modeling of a set of synthetic regulatory sequences challenges this assumption.

Original languageEnglish (US)
Pages (from-to)236-245
Number of pages10
JournalCell Reports
Volume21
Issue number1
DOIs
StatePublished - Oct 3 2017

Keywords

  • bag of sites model
  • enhancer
  • enhancer-level model
  • fused enhancer
  • locus-level model
  • quenching model
  • thermodynamic model
  • two-tier model

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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