Predictive modeling reveals that higher-order cooperativity drives transcriptional repression in a synthetic developmental enhancer

Authors:
Open Access
Publisher website
Google Scholar
Abstract
A challenge in quantitative biology is to predict output patterns of gene expression from knowledge of input transcription factor patterns and from the arrangement of binding sites for these transcription factors on regulatory DNA. We tested whether widespread thermodynamic models could be used to infer parameters describing simple regulatory architectures that inform parameter-free predictions of more complex enhancers in the context of transcriptional repression by Runt in the early fruit fly embryo. By modulating the number and placement of Runt binding sites within an enhancer, and quantifying the resulting transcriptional activity using live imaging, we discovered that thermodynamic models call for higher-order cooperativity between multiple molecular players. This higher-order cooperativity captures the combinatorial complexity underlying eukaryotic transcriptional regulation and cannot be determined from simpler regulatory architectures, highlighting the challenges in reaching a predictive understanding of transcriptional regulation in eukaryotes and calling for approaches that quantitatively dissect their molecular nature.
All Related Versions
Funding Information
  • Burroughs Wellcome Fund (Career Award)
  • Sloan Research Foundation
  • Human Frontier Science Program
  • Searle Scholars Program
  • Shurl and Kay Curci Foundation
  • Hellman Foundation
  • National Institute of Health (DP2 OD024541-01)
  • National Science Foundation (1652236)
  • Korea Foundation for Advanced Studies (Graduate Student Fellowship)
  • Chan Zuckerberg Biohub (Chan Zuckerberg Biohub Investigator Award)

This publication has 89 references indexed in Scilit: