用扩散Transformer生成大肠杆菌三维基因组,让结构符合染色体接触数据。
Contact-Guided 3D Genome Structure Generation of E. coli via Diffusion Transformers
- 通过扩散Transformer建模,从接触图生成多样化的三维结构
- 生成结构的平均接触模式与输入Hi-C数据高度一致
- 适合研究基因组空间构象的多样性与物理可解释性
本文提出一种基于条件扩散-变压器框架的三维大肠杆菌基因组结构生成方法,以Hi-C接触图作为指导。不同于生成单一确定结构,该方法将基因组重构视为条件生成问题,采样出一组异质性结构,其平均接触模式与输入的Hi-C数据一致。利用粗粒度分子动力学模拟构建合成数据集,生成具有环形拓扑的染色质集合及其对应的Hi-C图谱。模型在潜在扩散设置中运行,采用变分自编码器保持每箱对齐并支持复制感知表示。通过基于变压器的编码器和交叉注意力机制注入Hi-C信息,实现从Hi-C到结构的物理可解释单向约束。使用流匹配目标进行稳定优化。在保留外层集合上的测试中,生成结构准确再现了输入的Hi-C距离衰减与结构相关性指标,同时保持显著的构象多样性,证明了基于扩散的生成建模在群体级三维基因组重构中的有效性。
原文摘要 · Abstract (English)
In this study, we present a conditional diffusion-transformer framework for generating ensembles of three-dimensional Escherichia coli genome conformations guided by Hi-C contact maps. Instead of producing a single deterministic structure, we formulate genome reconstruction as a conditional generative modeling problem that samples heterogeneous conformations whose ensemble-averaged contacts are consistent with the input Hi-C data. A synthetic dataset is constructed using coarse-grained molecular dynamics simulations to generate chromatin ensembles and corresponding Hi-C maps under circular topology. Our models operate in a latent diffusion setting with a variational autoencoder that preserves per-bin alignment and supports replication-aware representations. Hi-C information is injected through a transformer-based encoder and cross-attention, enforcing a physically interpretable one-way constraint from Hi-C to structure. The model is trained using a flow-matching objective for stable optimization. On held-out ensembles, generated structures reproduce the input Hi-C distance-decay and structural correlation metrics while maintaining substantial conformational diversity, demonstrating the effectiveness of diffusion-based generative modeling for ensemble-level 3D genome reconstruction.
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