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

ABSTRACT: 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.

SUBMITTER: Choi J

PROVIDER: S-EPMC8004103 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

Project description: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.

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