美国哈佛大学医学院Sun Hur研究团队揭示Aire控制转录凝聚体组装的机制。这一研究成果于2024年8月21日在线发表在国际学术期刊《自然—免疫学》上。

研究人员报道了自身免疫调节因子（Aire）介导的转录凝聚体组装的多层次机制。Aire是一个必需的转录调节因子，负责中央T细胞耐受性的基因表达重编程。Aire凝聚体在增强子上组装，刺激局部转录活动，并连接不同染色体间的位点。这种功能性凝聚体的形成依赖于Aire的三个结构域之间的协调：聚合结构域——半胱天冬酶激活募集结构域（CARD）、组蛋白结合结构域——第一个植物同源结构域（PHD1）和C端尾部（CTT）。

具体来说，CTT与共激活因子CBP/p300结合，将Aire招募到富含CBP/p300的增强子上，促进CARD介导的凝聚体组装。相反，PHD1与广泛存在的组蛋白标记H3K4me0结合，使Aire分散在整个基因组中，直到Aire在增强子上核化。该研究表明，PHD1介导的抑制与CTT介导的Aire聚合刺激之间的平衡对于在靶标位点形成具有转录活性的凝聚体至关重要，这为转录调控因子的受控聚合提供了新的见解。

研究人员表示，转录凝聚体在基因表达和调控中发挥着关键作用，但其组装机制仍未得到充分理解。

附：英文原文

Title: Mechanism for controlled assembly of transcriptional condensates by Aire

Author: Huoh, Yu-San, Zhang, Qianxia, Trner, Ricarda, Baca, Sylvan C., Arthanari, Haribabu, Hur, Sun

Issue&Volume: 2024-08-21

Abstract: Transcriptional condensates play a crucial role in gene expression and regulation, yet their assembly mechanisms remain poorly understood. Here, we report a multi-layered mechanism for condensate assembly by autoimmune regulator (Aire), an essential transcriptional regulator that orchestrates gene expression reprogramming for central T cell tolerance. Aire condensates assemble on enhancers, stimulating local transcriptional activities and connecting disparate inter-chromosomal loci. This functional condensate formation hinges upon the coordination between three Aire domains: polymerization domain caspase activation recruitment domain (CARD), histone-binding domain (first plant homeodomain (PHD1)), and C-terminal tail (CTT). Specifically, CTT binds coactivators CBP/p300, recruiting Aire to CBP/p300-rich enhancers and promoting CARD-mediated condensate assembly. Conversely, PHD1 binds to the ubiquitous histone mark H3K4me0, keeping Aire dispersed throughout the genome until Aire nucleates on enhancers. Our findings showed that the balance between PHD1-mediated suppression and CTT-mediated stimulation of Aire polymerization is crucial to form transcriptionally active condensates at target sites, providing new insights into controlled polymerization of transcriptional regulators.

DOI: 10.1038/s41590-024-01922-w

Source: https://www.nature.com/articles/s41590-024-01922-w