Phase separation of YAP-MAML2 differentially regulates the transcriptome

• 成果类型: Article
• 署名作者: Chung, Chan-, I; Yang, Junjiao; Yang, Xiaoyu; Liu, Hongjiang; Ma, Zhimin; Szulzewsky, Frank; Holland, Eric C.; Shen, Yin; Shu, Xiaokun
• 署名单位: University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Fred Hutchinson Cancer Center; Fred Hutchinson Cancer Center
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11903
• DOI: 10.1073/pnas.2310430121
• 发表日期: 2024-02-13
• 关键词: fluorescent protein; in-vivo; activation; repression; initiation; PATHWAY; size

摘要

Phase separation (PS) drives the formation of biomolecular condensates that are emerging biological structures involved in diverse cellular processes. Recent studies have unveiled PS- induced formation of several transcriptional factor (TF) condensates that are transcriptionally active, but how strongly PS promotes gene activation remains unclear. Here, we show that the oncogenic TF fusion Yes- associated protein 1- Mastermind like transcriptional coactivator 2 (YAP- MAML2) undergoes PS and forms liquid - like condensates that bear the hallmarks of transcriptional activity. Furthermore, we examined the contribution of PS to YAP- MAML2- mediated gene expression by developing a chemogenetic tool that dissolves TF condensates, allowing us to compare phase- separated and non- phase- separated conditions at identical YAP-MAML2 protein levels. We found that a small fraction of YAP- MAML2- regulated genes is further affected by PS, which include the canonical YAP target genes CTGF and CYR61 , and other oncogenes. On the other hand, majority of YAP- MAML2- regulated genes are not affected by PS, highlighting that transcription can be activated effectively by diffuse complexes of TFs with the transcriptional machinery. Our work opens new directions in understanding the role of PS in selective modulation of gene expression, suggesting differential roles of PS in biological processes.