Co-condensation between transcription factor and coactivator p300 modulates transcriptional bursting kinetics

• Published in: Molecular cell 2021-04, Vol.81 (8), p.1682-1697.e7
• Main Authors: Ma, Liang, Gao, Zeyue, Wu, Jiegen, Zhong, Bijunyao, Xie, Yuchen, Huang, Wen, Lin, Yihan
• Format: Article
• Language: English
• Subjects: Acetylation; Animals; biomolecular condensation; Cell Line; CHO Cells; cooperativity; CREB-Binding Protein - metabolism; Cricetulus; E1A-Associated p300 Protein - metabolism; Gene Expression Regulation - genetics; gene regulation; HEK293 Cells; Histones - metabolism; Humans; Kinetics; live-cell imaging; Mice; nonlinear dose response; p300; Trans-Activators - metabolism; Transcription Factors - metabolism; Transcription, Genetic - genetics; Transcriptional Activation - genetics; transcriptional bursting; transcriptional imaging
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2021.01.031

The coactivator p300/CREB-binding protein (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 can orchestrate two functions through the formation of dynamic clusters with certain transcription factors (TFs), which is mediated by the interactions between a TF’s transactivation domain (TAD) and the intrinsically disordered regions of p300. Co-condensation can enable spatially defined, all-or-none activation of p300’s catalytic activity, priming the recruitment of coactivators, including Brd4. We showed that co-condensation can modulate transcriptional initiation rate and burst duration of target genes, underlying nonlinear gene regulatory functions. Such modulation is consistent with how p300 might shape gene bursting kinetics globally. Altogether, these results suggest an intriguing gene regulation mechanism, in which TF and p300 co-condensation contributes to transcriptional bursting regulation and cooperative gene control. [Display omitted] •Some transcription factors can recruit p300 by co-condensation•Interactions between disordered regions of TF and p300 can drive co-condensation•Co-condensation can promote p300 transactivation and stabilize TF-p300 assembly•Transcriptional bursting and dose-response curve are modulated by co-condensation Ma et al. demonstrate that transcription factor and coactivator p300 can cocondense. They systematically dissect the mechanism and function of co-condensation. The findings offer quantitative insights into how p300 catalytic activity, gene transcriptional bursting, and gene dose-response curve can be regulated by co-condensation.