WhichTF is dominant in your open chromatin data?

We present WhichTF, a computational method to identify functionally important transcription factors (TFs) from chromatin accessibility measurements. To rank TFs, WhichTF applies an ontology-guided functional approach to compute novel enrichment by integrating accessibility measurements, high-confidence pre-computed conservation-aware TF binding sites, and putative gene-regulatory models. Comparison with prior sheer abundance-based methods reveals the unique ability of WhichTF to identify context-specific TFs with functional relevance, including NF-κB family members in lymphocytes and GATA factors in cardiac cells. To distinguish the transcriptional regulatory landscape in closely related samples, we apply differential analysis and demonstrate its utility in lymphocyte, mesoderm developmental, and disease cells. We find suggestive, under-characterized TFs, such as RUNX3 in mesoderm development and GLI1 in systemic lupus erythematosus. We also find TFs known for stress response, suggesting routine experimental caveats that warrant careful consideration. WhichTF yields biological insight into known and novel molecular mechanisms of TF-mediated transcriptional regulation in diverse contexts, including human and mouse cell types, cell fate trajectories, and disease-associated cells.