Evidence for additive and synergistic action of mammalian enhancers during cell fate determination

Enhancer activity is known to drive cell differentiation and cell type determination, but it remains unclear how enhancers cooperate during these processes. Here we investigate enhancer cooperation during transdifferentiation of human B-cells to macrophages using enhancer RNA synthesis from accessible, H3K4-monomethylated chromatin regions as a proxy for enhancer activity. Most enhancers cooperate in an additive way to induce transcription of target genes. However, at ~130 loci, enhancers cooperate synergistically, changing activity of target genes exponentially over time. The latter genes are cell type-specific, indicating that enhancer synergy can drive differentiation and cell type determination. Pioneering factor occupancy, DNA accessibility profiling and eRNA synthesis reveal the temporal order of events that lead to enhancer synergy. Our results are consistent with a condensation model for transcription activation of cell type-specific genes that involves simultaneous contacts of multiple enhancers with their target promoter. Refer to individual Series