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<p>Though open chromatin may promote active transcription, gene expression responses may not be directly coordinated with changes in chromatin accessibility. Most existing methods for single-cell multi-omics data focus only on learning stationary, shared information among these modalities, overlooking modality-specific information delineating cellular states and dynamics resulting from causal relations among modalities. To address this, the epigenome-transcriptome relationship can be characterized in relation to time as coupled (changing dependently) or decoupled (changing independently). We propose the framework HALO, adopting a causal approach to model these temporal causal relations on two levels. On the representation level, HALO factorizes these two modalities into both coupled and decoupled latent representations, revealing their dynamic interplay. On the individual gene level, HALO matches gene-peak pairs and characterizes their changes over time. HALO discovers analogous biological functions between modalities, distinguishes epigenetic factors for lineage specification, and identifies temporal <i>cis</i>-regulation interactions relevant to cellular differentiation and human diseases.</p>

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HALO: hierarchical causal modeling for single cell multi-omics data

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月7日

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  • Haiyi Mao,
  • Minxue Jia,
  • Marissa Di,
  • Eleanor Valenzi,
  • Xiaoyu Tracy Cai,
  • Robert Lafyatis,
  • Kun Zhang,
  • Panayiotis V. Benos

摘要

Though open chromatin may promote active transcription, gene expression responses may not be directly coordinated with changes in chromatin accessibility. Most existing methods for single-cell multi-omics data focus only on learning stationary, shared information among these modalities, overlooking modality-specific information delineating cellular states and dynamics resulting from causal relations among modalities. To address this, the epigenome-transcriptome relationship can be characterized in relation to time as coupled (changing dependently) or decoupled (changing independently). We propose the framework HALO, adopting a causal approach to model these temporal causal relations on two levels. On the representation level, HALO factorizes these two modalities into both coupled and decoupled latent representations, revealing their dynamic interplay. On the individual gene level, HALO matches gene-peak pairs and characterizes their changes over time. HALO discovers analogous biological functions between modalities, distinguishes epigenetic factors for lineage specification, and identifies temporal cis-regulation interactions relevant to cellular differentiation and human diseases.