Motivation: Transcription factor (TF) coordination plays a key role in gene regulation via direct and/or indirect protein-protein interactions (PPIs) and co-binding to regulatory elements on DNA. Single-cell technologies facilitate gene expression measurement for individual cells and cell-type identification, yet the connection between TF-TF coordination and target gene (TG) regulation of various cell types remains unclear.

Results: To address this, we introduce our innovative computational approach, Network Regression Embeddings (NetREm), to reveal cell-type TF-TF coordination activities for TG regulation. NetREm leverages network-constrained regularization, using prior knowledge of PPIs among TFs, to analyze single-cell gene expression data, uncovering cell-type coordinating TFs and identifying revolutionary TF-TG candidate regulatory network links. NetREm's performance is validated using simulation studies and benchmarked across several datasets in humans, mice, yeast. Further, we showcase NetREm's ability to prioritize valid novel human TF-TF coordination links in 9 peripheral blood mononuclear and 42 immune cell sub-types. We apply NetREm to examine cell-type networks in central and peripheral nerve systems (e.g. neuronal, glial, Schwann cells) and in Alzheimer's disease versus Controls. Top predictions are validated with experimental data from rat, mouse, and human models. Additional functional genomics data helps link genetic variants to our TF-TG regulatory and TF-TF coordination networks.

Availability and implementation: https://github.com/SaniyaKhullar/NetREm.

• PMID: 40260118
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Journal Article

Authors

Khullar S, Huang X, Ramesh R, Svaren J, Wang D

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