Uncoupling evolutionary changes in DNA sequence, transcription factor occupancy and enhancer activity

Pierre Khoueiry, Charles Girardot, Lucia Ciglar, Pei Chen Peng, E. Hilary Gustafson, Saurabh Sinha, Eileen E.M. Furlong

Research output: Contribution to journalArticlepeer-review


Sequence variation within enhancers plays a major role in boThevolution and disease, yet its functional impact on transcription factor (TF) occupancy and enhancer activity remains poorly understood. Here, we assayed the binding of five essential TFs over multiple stages of embryogenesis in two distant Drosophila species (with 1.4 substitutions per neutral site), identifying thousands of orthologous enhancers with conserved or diverged combinatorial occupancy. We used these binding signatures to dissect two properties of developmental enhancers: (1) potential TF cooperativity, using signatures of co-associations and co-divergence in TF occupancy. This revealed conserved combinatorial binding despite sequence divergence, suggesting protein-protein interactions sustain conserved collective occupancy. (2) Enhancer in-vivo activity, revealing orthologous enhancers with conserved activity despite divergence in TF occupancy. Taken together, we identify enhancers with diverged motifs yet conserved occupancy and others with diverged occupancy yet conserved activity, emphasising the need to functionally measure the effect of divergence on enhancer activity.

Original languageEnglish (US)
Article numbere28440
StatePublished - Aug 9 2017

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)


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