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ChromatinHD connects single-cell DNA accessibility and conformation to gene expression through scale-adaptive machine learning

Author

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  • Wouter Saelens

    (Swiss Federal Institute of Technology (EPFL)
    Swiss Institute of Bioinformatics
    VIB Center for Inflammation Research)

  • Olga Pushkarev

    (Swiss Federal Institute of Technology (EPFL)
    Swiss Institute of Bioinformatics)

  • Bart Deplancke

    (Swiss Federal Institute of Technology (EPFL)
    Swiss Institute of Bioinformatics)

Abstract

Gene regulation is inherently multiscale, but scale-adaptive machine learning methods that fully exploit this property in single-nucleus accessibility data are still lacking. Here, we develop ChromatinHD, a pair of scale-adaptive models that uses the raw accessibility data, without peak-calling or windows, to link regions to gene expression and determine differentially accessible chromatin. We show how ChromatinHD consistently outperforms existing peak and window-based approaches and find that this is due to a large number of uniquely captured, functional accessibility changes within and outside of putative cis-regulatory regions. Furthermore, ChromatinHD can delineate collaborating regulatory regions, including their preferential genomic conformations, that drive gene expression. Finally, our models also use changes in ATAC-seq fragment lengths to identify dense binding of transcription factors, a feature not captured by footprinting methods. Altogether, ChromatinHD, available at https://chromatinhd.org , is a suite of computational tools that enables a data-driven understanding of chromatin accessibility at various scales and how it relates to gene expression.

Suggested Citation

  • Wouter Saelens & Olga Pushkarev & Bart Deplancke, 2025. "ChromatinHD connects single-cell DNA accessibility and conformation to gene expression through scale-adaptive machine learning," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55447-9
    DOI: 10.1038/s41467-024-55447-9
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