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scooby: modeling multimodal genomic profiles from DNA sequence at single-cell resolution.

Johannes C Hingerl1,2, Laura D Martens1,3, Alexander Karollus1,2

  • 1School of Computation, Information and Technology, Technical University of Munich, Munich, Germany.

Nature Methods
|October 22, 2025
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Summary
This summary is machine-generated.

A new computational framework, scooby, models gene regulation in single cells. It integrates RNA sequencing and epigenomic data to reveal cell-specific gene expression patterns and regulatory elements.

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Area of Science:

  • Genomics
  • Molecular Biology
  • Computational Biology

Background:

  • Understanding gene regulation at single-cell resolution is crucial for deciphering cellular heterogeneity.
  • Existing models often fail to capture dynamic processes and cell-specific variations revealed by multimodal single-cell technologies.
  • There is a need for computational tools that can integrate single-cell RNA sequencing and epigenomic data.

Purpose of the Study:

  • To introduce scooby, a novel framework for modeling genomic profiles at single-cell resolution.
  • To enable the analysis of sequence determinants across gene expression steps in individual cells.
  • To bridge the gap between bulk omics data analysis and single-cell multimodal data.

Main Methods:

  • Developed scooby, a framework integrating single-cell RNA sequencing (scRNA-seq) coverage and single-cell Assay for Transposase-Accessible Chromatin using sequencing (scATAC-seq) data.
  • Leveraged the Borzoi multiomics profile predictor, enhanced with a cell-specific decoder.
  • Applied the framework to model genomic profiles at single-cell resolution.

Main Results:

  • Scooby successfully recapitulates cell-specific expression levels for genes not used in training.
  • The framework identifies regulatory elements and their putative target genes with high accuracy.
  • Scooby resolves single-cell effects of expression quantitative trait loci (eQTLs), detailing their impact on chromatin accessibility and gene expression.

Conclusions:

  • Scooby provides a powerful new tool for dissecting gene regulation at the resolution of individual cells.
  • The framework advances the analysis of multimodal single-cell omics data.
  • Scooby is expected to significantly aid in unraveling the complexities of gene regulatory networks in cellular populations.