{"title":"Promoter DNA methylation and transcription factor condensation are linked to transcriptional memory in mammalian cells.","authors":"Shenqi Fan, Liang Ma, Chengzhi Song, Xu Han, Bijunyao Zhong, Yihan Lin","doi":"10.1016/j.cels.2024.08.007","DOIUrl":null,"url":null,"abstract":"<p><p>The regulation of genes can be mathematically described by input-output functions that are typically assumed to be time invariant. This fundamental assumption underpins the design of synthetic gene circuits and the quantitative understanding of natural gene regulatory networks. Here, we found that this assumption is challenged in mammalian cells. We observed that a synthetic reporter gene can exhibit unexpected transcriptional memory, leading to a shift in the dose-response curve upon a second induction. Mechanistically, we investigated the cis-dependency of transcriptional memory, revealing the necessity of promoter DNA methylation in establishing memory. Furthermore, we showed that the synthetic transcription factor's effective DNA binding affinity underlies trans-dependency, which is associated with its capacity to undergo biomolecular condensation. These principles enabled modulating memory by perturbing either cis- or trans-regulation of genes. Together, our findings suggest the potential pervasiveness of transcriptional memory and implicate the need to model mammalian gene regulation with time-varying input-output functions. A record of this paper's transparent peer review process is included in the supplemental information.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"808-823.e6"},"PeriodicalIF":0.0000,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell systems","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.cels.2024.08.007","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/6 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
The regulation of genes can be mathematically described by input-output functions that are typically assumed to be time invariant. This fundamental assumption underpins the design of synthetic gene circuits and the quantitative understanding of natural gene regulatory networks. Here, we found that this assumption is challenged in mammalian cells. We observed that a synthetic reporter gene can exhibit unexpected transcriptional memory, leading to a shift in the dose-response curve upon a second induction. Mechanistically, we investigated the cis-dependency of transcriptional memory, revealing the necessity of promoter DNA methylation in establishing memory. Furthermore, we showed that the synthetic transcription factor's effective DNA binding affinity underlies trans-dependency, which is associated with its capacity to undergo biomolecular condensation. These principles enabled modulating memory by perturbing either cis- or trans-regulation of genes. Together, our findings suggest the potential pervasiveness of transcriptional memory and implicate the need to model mammalian gene regulation with time-varying input-output functions. A record of this paper's transparent peer review process is included in the supplemental information.
基因的调控可以用输入-输出函数进行数学描述,这些函数通常被假定为时间不变。这一基本假设是设计合成基因回路和定量理解天然基因调控网络的基础。在这里,我们发现这一假设在哺乳动物细胞中受到了挑战。我们观察到,合成报告基因会表现出意想不到的转录记忆,导致剂量反应曲线在第二次诱导时发生移动。从机理上讲,我们研究了转录记忆的顺式依赖性,揭示了启动子 DNA 甲基化对建立记忆的必要性。此外,我们还发现合成转录因子的有效 DNA 结合亲和力是反式依赖性的基础,而反式依赖性与其进行生物分子缩聚的能力有关。这些原理使我们能够通过干扰基因的顺式或反式调控来调节记忆。总之,我们的研究结果表明转录记忆具有潜在的普遍性,并暗示了利用时变输入-输出功能来模拟哺乳动物基因调控的必要性。本文的同行评审过程透明,其记录见补充信息。