Krieger Spencer, Haber Ellie, Ma Jian
Ray and Stephanie Lane Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
Machine Learning Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
bioRxiv. 2025 May 23:2025.05.19.654884. doi: 10.1101/2025.05.19.654884.
Understanding how transcription factors (TFs) orchestrate gene regulatory networks that define complex tissue structures is central to uncovering tissue organization and disease mechanisms. Although spatial multiome technologies now enable measurement of both transcriptional activity and chromatin accessibility, existing computational methods either overlook spatial tissue context or are hindered by the high dropout rates characteristic of such data. Here, we introduce Eykthyr, a computational framework that integrates gene expression and chromatin accessibility within a spatially aware model to identify TFs driving spatial gene programs. Eykthyr mitigates dropout effects by leveraging interpretable, low-dimensional embeddings of gene expression and chromatin accessibility - both linear with respect to their input - enabling robust identification and scalable inference of spatial transcriptional regulators. Applied across diverse spatial multiome datasets, Eykthyr consistently outperforms existing approaches, accurately identifying TFs that coordinate spatial gene programs in mouse brain development and regulate T-cell states within tumor microenvironments. Eykthyr establishes a foundation for decoding how TFs interpret local intercellular signaling to shape tissue structure, offering insights into the regulatory logic underlying spatial organization in health and disease.
理解转录因子（TFs）如何协调定义复杂组织结构的基因调控网络，对于揭示组织构成和疾病机制至关重要。尽管空间多组学技术现在能够测量转录活性和染色质可及性，但现有的计算方法要么忽略了空间组织背景，要么受到此类数据高缺失率的阻碍。在这里，我们介绍了Eykthyr，这是一个计算框架，它在一个空间感知模型中整合基因表达和染色质可及性，以识别驱动空间基因程序的转录因子。Eykthyr通过利用基因表达和染色质可及性的可解释低维嵌入来减轻缺失效应——两者相对于其输入都是线性的——从而能够可靠地识别和可扩展地推断空间转录调节因子。应用于各种空间多组学数据集时，Eykthyr始终优于现有方法，准确识别在小鼠大脑发育中协调空间基因程序并调节肿瘤微环境内T细胞状态的转录因子。Eykthyr为解码转录因子如何解释局部细胞间信号传导以塑造组织结构奠定了基础，为健康和疾病中空间组织的调控逻辑提供了见解。
