Evidence of widespread, independent sequence signature for transcription factor cobinding

Transcription factors (TFs) are the vocabulary that genomes use to regulate gene expression and phenotypes. The interactions among TFs enrich this vocabulary and orchestrate diverse biological processes. Although simple models identify open chromatin and the presence of TF motifs as the two major contributors to TF binding patterns, it remains elusive what contributes to the in vivo TF cobinding landscape. In this study, we developed a machine learning algorithm to explore the contributors of the cobinding patterns. The algorithm substantially outperforms the state-of-the-field models for TF cobinding prediction. Game theory-based feature importance analysis reveals that, for most of the TF pairs we studied, independent motif sequences contribute one or more of the two TFs under investigation to their cobinding patterns. Such independent motif sequences include, but are not limited to, transcription initiation-related proteins and known TF complexes. We found the motif sequence signatures and the TFs are rarely mutual, corroborating a hierarchical and directional organization of the regulatory network and refuting the possibility of artifacts caused by shared sequence similarity with the TFs under investigation. We modeled such regulatory language with directed graphs, which reveal shared, global factors that are related to many binding and cobinding patterns.