Chromatin accessibility in the Drosophila embryo is determined by transcription factor pioneering and enhancer activation

Kaelan J. Brennan, Melanie Weilert, Sabrina Krueger, Anusri Pampari, Hsiao yun Liu, Ally W.H. Yang, Jason A. Morrison, Timothy R. Hughes, Christine A. Rushlow, Anshul Kundaje, Julia Zeitlinger

Research output: Contribution to journalArticlepeer-review


Chromatin accessibility is integral to the process by which transcription factors (TFs) read out cis-regulatory DNA sequences, but it is difficult to differentiate between TFs that drive accessibility and those that do not. Deep learning models that learn complex sequence rules provide an unprecedented opportunity to dissect this problem. Using zygotic genome activation in Drosophila as a model, we analyzed high-resolution TF binding and chromatin accessibility data with interpretable deep learning and performed genetic validation experiments. We identify a hierarchical relationship between the pioneer TF Zelda and the TFs involved in axis patterning. Zelda consistently pioneers chromatin accessibility proportional to motif affinity, whereas patterning TFs augment chromatin accessibility in sequence contexts where they mediate enhancer activation. We conclude that chromatin accessibility occurs in two tiers: one through pioneering, which makes enhancers accessible but not necessarily active, and the second when the correct combination of TFs leads to enhancer activation.

Original languageEnglish (US)
Pages (from-to)1898-1916.e9
JournalDevelopmental Cell
Issue number19
StatePublished - Oct 9 2023


  • ATAC-seq
  • BPNet
  • ChIP-nexus
  • Drosophila development
  • Zelda
  • chromatin accessibility
  • enhancers
  • interpretable deep learning
  • pioneer factors
  • transcription factors

ASJC Scopus subject areas

  • Molecular Biology
  • General Biochemistry, Genetics and Molecular Biology
  • Developmental Biology
  • Cell Biology


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