CoTF-reg reveals cooperative transcription factors in oligodendrocyte gene regulation using single-cell multi-omics

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Oligodendrocytes are the myelinating cells within the central nervous system, but the mechanisms by which transcription factors (TFs) cooperate for gene regulation in oligodendrocytes remain unclear. We introduce coTF-reg, an analytical framework that integrates scRNA-seq and scATAC-seq data to identify cooperative TFs co-regulating the target gene (TG). First, we identify co-binding TF pairs in the same oligodendrocyte-specific regulatory regions. Next, we train a deep learning model to predict each TG expression using the co-binding TFs’ expressions. Shapley interaction scores reveal high interactions between co-binding TF pairs, such as SOX10-TCF12. Validation using oligodendrocyte eQTLs and their eGenes that are regulated by these cooperative TFs show potential regulatory roles for genetic variants. Experimental validation using ChIP-seq data confirms some cooperative TF pairs, such as SOX10-OLIG2. Prediction performance of our models is evaluated through holdout data and additional datasets, and an ablation study is also conducted. The results demonstrate stable and consistent performance.