Developmental and housekeeping transcriptional programs display distinct modes of enhancer-enhancer cooperativity in Drosophila

Genomic enhancers are key transcriptional regulators which, upon the binding of sequence-specific transcription factors, can activate their cognate promoter. Although enhancers have been extensively studied in isolation, a substantial number of genes have more than one simultaneously active enhancer, and it remains unclear how these distinct elements cooperate to regulate transcription. In this work, we report that developmental enhancers – that regulate tissue-specific genes – and housekeeping enhancers rely on distinct modes of enhancer-enhancer cooperativity: while developmental enhancers are synergistic, housekeeping enhancers are additive (meaning that their combined activity mirrors the sum of their individual activities). Developmental enhancer synergy is promiscuous in our system and is not associated with specific combinations of transcription factors. However, developmental transcription factors globally contain higher fraction of intrinsically disordered domains, which might support such synergistic interactions. The enhancer activity of three different pools of enhancer-enhancer pairs were measured using the STARR-Seq method in Drosophila S2 cells (with or without ecdysone) and OSC cells.

基因组增强子（Genomic enhancers）是关键的转录调控因子，在结合序列特异性转录因子（sequence-specific transcription factors）后可激活其同源启动子（cognate promoter）。尽管学界已对增强子开展了大量单独研究，但仍有大量基因拥有多个同时处于活跃状态的增强子，目前尚不清楚这些不同的调控元件如何协同调控转录。本研究发现，调控组织特异性基因（tissue-specific genes）的发育增强子（developmental enhancers）与持家增强子（housekeeping enhancers）依赖于截然不同的增强子-增强子协同作用模式：发育增强子呈现协同增效效应，而持家增强子则表现为加和性作用，即二者的联合活性等于各自单独活性的总和。在本研究体系中，发育增强子的协同作用并无特异性，且与特定的转录因子组合无关。不过，发育类转录因子整体上含有更高比例的内在无序结构域（intrinsically disordered domains），这或许可支持这类协同相互作用。本研究通过STARR-Seq方法，在果蝇S2细胞（Drosophila S2 cells，添加或不添加蜕皮激素（ecdysone））以及OSC细胞（OSC cells）中，对三类不同增强子-增强子配对的调控活性进行了检测。