coTRaCTE predicts co-occurring transcription factors within cell-type specific enhancers

Alena van Bömmel, Michael I. Love, Ho-Ryun Chung, Martin Vingron

Abstract: Author summary Differentiation of multicellular organisms into a variety of cell types with different morphology and function is the result of cell-type specific gene expression. The most important regulators of gene expression are transcription factors (TFs) binding to cis-regulatory sequences, such as enhancers or promoters. In particular, the combinatorial cooperativity of TFs is essential for defining the cell-type specificity. However, the experimental detection of cooperative TFs on a large scale is very difficult. Here, we develop a new strategy for predicting co-occurring TFs in a cell-type specific manner. We use a simple statistical test of TF co-binding between cell-type specific enhancers and globally active regulatory regions which assures the specificity and significance of predicted TF co-occurrences. Using chromatin accessibility data in 90 cell lines enables us to predict more than 2000 co-occurring TF pairs in 64 cell types. We confirm our predictions by multiple means, including comparison with large-scale experimental data. Based on our method, we obtain new insights into the cell-type specific TF cooperativity, and the complexity of transcriptional regulatory mechanisms.