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<p>The DNA binding of most <i>Escherichia coli</i> Transcription Factors (TFs) has not been comprehensively mapped, and few have models that can quantitatively predict binding affinity. We report the global mapping of in vivo DNA binding for 139 <i>E. coli</i> TFs using ChIP-Seq. We use these data to train BoltzNet, a novel neural network that predicts TF binding energy from DNA sequence. BoltzNet mirrors a quantitative biophysical model and provides directly interpretable predictions genome-wide at nucleotide resolution. We use BoltzNet to quantitatively design novel binding sites, which we validate with biophysical experiments on purified protein. We generate models for 124 TFs that provide insight into global features of TF binding, including clustering of sites, the role of accessory bases, the relevance of weak sites, and the background affinity of the genome. Our paper provides new paradigms for studying TF-DNA binding and for the development of biophysically motivated neural networks.</p>

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Predictive biophysical neural network modeling of a compendium of in vivo transcription factor DNA binding profiles for Escherichia coli

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月7日

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  • Patrick Lally,
  • Laura Gómez-Romero,
  • Víctor H. Tierrafría,
  • Patricia Aquino,
  • Claire Rioualen,
  • Xiaoman Zhang,
  • Sunyoung Kim,
  • Gabriele Baniulyte,
  • Jonathan Plitnick,
  • Carol Smith,
  • Mohan Babu,
  • Julio Collado-Vides,
  • Joseph T. Wade,
  • James E. Galagan

摘要

The DNA binding of most Escherichia coli Transcription Factors (TFs) has not been comprehensively mapped, and few have models that can quantitatively predict binding affinity. We report the global mapping of in vivo DNA binding for 139 E. coli TFs using ChIP-Seq. We use these data to train BoltzNet, a novel neural network that predicts TF binding energy from DNA sequence. BoltzNet mirrors a quantitative biophysical model and provides directly interpretable predictions genome-wide at nucleotide resolution. We use BoltzNet to quantitatively design novel binding sites, which we validate with biophysical experiments on purified protein. We generate models for 124 TFs that provide insight into global features of TF binding, including clustering of sites, the role of accessory bases, the relevance of weak sites, and the background affinity of the genome. Our paper provides new paradigms for studying TF-DNA binding and for the development of biophysically motivated neural networks.