Koska Mervenaz, Swigut Tomek, Boettiger Alistair Nicol, Wysocka Joanna
Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
bioRxiv. 2025 May 7:2025.05.06.652547. doi: 10.1101/2025.05.06.652547.
Competition between promoters within a shared regulatory landscape has been implicated in development and disease, but the determinants of promoter competition have not been systematically studied. Here, we use a synthetic platform to introduce diverse promoters at defined genomic sites within the locus and measure how these inserted promoters attenuate activity of the endogenous promoter. We find that reduction in endogenous transcription is correlated with the strength of the inserted promoter. Transcription from the inserted promoter is required for competition, with longer transcript resulting in more competition. Furthermore, competition is dependent on the location of the inserted promoter, but independent of cohesin mediated loop extrusion. Lastly, we encounter silencing of the inserted promoter by HUSH, which counteracts competition. Together, our work uncovers the rules governing promoter competition, highlights its impact on tuning gene expression levels, and suggests a role for RNA in mediating this process.
共享调控环境中启动子之间的竞争与发育和疾病有关，但启动子竞争的决定因素尚未得到系统研究。在这里，我们使用一个合成平台在 基因座内的特定基因组位点引入不同的启动子，并测量这些插入的启动子如何减弱内源性启动子的活性。我们发现内源性转录的减少与插入启动子的强度相关。插入启动子的转录对于竞争是必需的，转录本越长，竞争越激烈。此外，竞争取决于插入启动子的位置，但与黏连蛋白介导的环挤压无关。最后，我们发现插入的启动子会被HUSH沉默，这抵消了竞争。总之，我们的工作揭示了控制启动子竞争的规则，突出了其对调节基因表达水平的影响，并表明RNA在介导这一过程中发挥作用。
