Co-condensation between transcription factor and coactivator p300 modulates transcriptional bursting kinetics. Ma et al.

The coactivator p300/CBP regulates genes by facilitating the assembly of transcriptional machinery and by acetylating histones and other factors. However, it remains mostly unclear how both functions of p300 are dynamically coordinated during gene control. Here, we showed that p300 appears to orchestrate two functions through the formation of dynamic co-condensates with certain transcription factors (TFs), which is mediated by the interactions between the TF’s trans-activation domain (TAD) and the intrinsically disordered regions (IDRs) of p300. Co-condensation enables spatially defined, all-or-none activation of p300’s catalytic activity, priming the recruitment of other coactivators including Brd4. We further revealed that co-condensation modulates transcriptional initiation rate and burst duration of target genes, underlying nonlinear and cooperative gene regulatory functions. Intriguingly, such modulation is consistent with how p300 shapes transcriptional bursting kinetics globally. Together, complementary lines of evidence suggest a new p300-meidated gene control mechanism, where TF and p300 co-condensation contributes to transcriptional bursting regulation and cooperative gene control.

共激活因子p300/CBP通过促进转录机器组装以及对组蛋白与其他因子进行乙酰化修饰来调控基因表达。然而，目前仍尚不明确p300的这两项功能在基因调控过程中是如何动态协同的。本研究表明，p300可通过与特定转录因子（Transcription Factors, TFs）形成动态共凝聚体来协调其两项功能，这一过程由转录因子的反式激活结构域（Trans-activation Domain, TAD）与p300的内在无序区域（Intrinsically Disordered Regions, IDRs）之间的相互作用所介导。共凝聚体可实现p300催化活性的空间限定性全或无式激活，进而促进包括Brd4在内的其他共激活因子的招募。本研究进一步揭示，共凝聚体可调控靶基因的转录起始速率与转录爆发持续时间，这一效应是非线性且具有协同性的基因调控功能的核心基础。有趣的是，此类调控模式与p300在全局范围内塑造转录爆发动力学的方式相一致。综上，一系列互补性实验证据共同指向了一种全新的p300介导的基因调控机制：即转录因子与p300的共凝聚体参与转录爆发调控与协同基因控制。