Material and source code for Kribelbauer et al. (https://www.biorxiv.org/content/10.1101/2023.05.05.539543v1).
In this project, we developed a novel approach leveraging enhancer-centric chromatin accessibility quantitative trait loci (caQTLs) to nominate cooperative, high concentration environments genome-wide. By analyzing TF binding signatures within the context of caQTLs and comparing episomal versus endogenous enhancer activities, we discovered a new class of regulators: ‘context-only’ TFs, whose binding sites (BSs) co-occur with those of cell type-specific pioneers, thereby boosting their activity. We show that the co-occurrence between these two types of TFs does not require a strict binding site syntax, suggesting that functional complementarity drives their co-enrichment. Context-only TFs are enriched in disordered protein domains, are associated with increased levels of coactivator binding, and lead to enhancer communication whenever they bind together with cell-type specific pioneers. Similar to Super Enhancers, context-only TFBS-enriched enhancers display sensitivity to transcriptional hub-disrupting molecules, supporting a key role for context-only TFs in establishing enhancer compatibility and hub assembly.