Evidence for additive and synergistic action of mammalian enhancers during cell fate determination.
Evidence for additive and synergistic action of mammalian enhancers during cell fate determination.
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DOI：
10.7554/elife.65381
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发表时间：
2021-03-26
期刊：
影响因子：
7.7
通讯作者：
Cramer P
中科院分区：
文献类型：
--
作者：
Choi J;Lysakovskaia K;Stik G;Demel C;Söding J;Tian TV;Graf T;Cramer P
增强子活性驱动细胞分化和细胞命运决定，但仍不清楚增强子在这些过程中如何合作。在这里，我们调查增强子合作过程中的人白血病B细胞转分化为巨噬细胞。通过结合先驱因子C/EBPα，随后染色质开放和增强子RNA（eRNA）从H3 K4-单甲基化区域合成来建立推定的增强子。使用eRNA合成作为增强子活性的代理，我们发现，大多数假定的增强子合作的添加剂的方式来调节指定的靶基因的转录。然而，从136个靶基因的转录指数依赖于其假定的配对增强子的活性总和，表明这些增强子协同合作。靶基因是细胞类型特异性的，这表明增强子协同作用可以有助于细胞命运决定。增强子协同作用似乎取决于细胞类型特异性转录因子，并且这种相互作用的增强子不能从用于检测超增强子的占用率或可及性数据中预测。
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.