TY - JOUR TI - Evidence for additive and synergistic action of mammalian enhancers during cell fate determination AU - Choi, Jinmi AU - Lysakovskaia, Kseniia AU - Stik, Gregoire AU - Demel, Carina AU - Söding, Johannes AU - Tian, Tian V AU - Graf, Thomas AU - Cramer, Patrick A2 - Ponting, Chris P A2 - Struhl, Kevin A2 - Singh, Harinder VL - 10 PY - 2021 DA - 2021/03/26 SP - e65381 C1 - eLife 2021;10:e65381 DO - 10.7554/eLife.65381 UR - https://doi.org/10.7554/eLife.65381 AB - Enhancer activity drives cell differentiation and cell fate determination, but it remains unclear how enhancers cooperate during these processes. Here we investigate enhancer cooperation during transdifferentiation of human leukemia B-cells to macrophages. Putative enhancers are established by binding of the pioneer factor C/EBPα followed by chromatin opening and enhancer RNA (eRNA) synthesis from H3K4-monomethylated regions. Using eRNA synthesis as a proxy for enhancer activity, we find that most putative enhancers cooperate in an additive way to regulate transcription of assigned target genes. However, transcription from 136 target genes depends exponentially on the summed activity of its putative paired enhancers, indicating that these enhancers cooperate synergistically. The target genes are cell type-specific, suggesting that enhancer synergy can contribute to cell fate determination. Enhancer synergy appears to depend on cell type-specific transcription factors, and such interacting enhancers are not predicted from occupancy or accessibility data that are used to detect superenhancers. KW - transdifferentiation KW - transcriptional regulation KW - enhancer cooperation KW - c/ebpa JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -