A pipeline to identify TF combinatorial binding uncovers TEAD1 as an antagonist of tissue-specific transcription factors in human organogenesis

Abstract

ABSTRACTGene expression is largely controlled by transcription factors (TFs), which bind to distal enhancers to facilitate recruitment of RNA Pol II at promoters. TFs bind to enhancers in combination with other TFs, a mechanism referred to as combinatorial binding. Although TF combinatorial binding is well established, the functional tissue-specific combinations of TFs at active enhancers during human embryonic development are under-explored. Here, we developed cocoTF, a pipeline to identify co-occurring TF motifs at context-specific regulatory regions using comprehensive bioinformatic tools and widely available H3K27ac ChIP-seq and RNA-seq data as input. We use cocoTF to explore co-occurring TF motifs in tissue-specific developmental enhancers of 11 human embryonic tissues. We identify a significant enrichment of recognition motifs for ubiquitous TFs in the vicinity of tissue-specific sequence signatures, pointing at universal patterns of TF functional connectivity in organ-specific transcriptional networks. We focused on TEAD TFs to address the functional role of ubiquitous TFs on cell type-specific transcriptional programs. Our results indicate that TEAD1, together with its coactivator YAP, attenuates tissue-specific enhancer activation, pointing at a broad effect of TEAD on cell type-specific transcriptional programs.