BRG1促进Treg活化：一个经典染色质重塑因子的新颖作用机制

调节性T细胞(Treg)只有在发生活化后，才能发挥作用。活化机制一直是免疫学的一个热点问题。我们发现，在Treg中敲除“ATP依赖性染色质重塑因子”Brg1, 能阻断Treg活化、诱发致死性炎症。令人意外的是，BRG1 ATPase点突变造成的症状要轻微得多，尽管点突变废除了BRG1的染色质重塑功能。这表明BRG1中隐藏着与染色质重塑无关但具有重大生理意义的新颖功能。本项目旨在揭秘这个新功能。与T细胞活化相关的关键基因，多由“超级增强子”(SE)调控；SE上，各种转录蛋白通过弱作用力互相吸引而凝聚成小液滴，这一“相变”过程浓集、区域化了转录蛋白，从而促成靶基因的高表达。多条线索提示，BRG1可推动上述相变而激活SE、推动Treg活化。我们拟利用独特的前期积累（包括自主研发的小鼠模型）和基因调控领域的最新技术，系统性地检验这一假说，有望获得横跨Treg和染色质两大研究领域的开拓性成果。

Regulatory T cells (Tregs) must undergo activation before they can function to maintain immune homeostasis。 The mechanism of Treg activation has remained a hot topic in the Treg field. We have discovered that the “ATP-dependent chromatin remodeling factor” Brg1 is crucial for Treg activation, because Treg-specific Brg1 deletion impairs Treg activation and trigger fatal autoimmunity. Surprisingly, a Brg1 ATPase point mutation, which abolishes its chromatin remodeling activity, produces much milder symptoms. The data not only indicate that BRG1 harbors Remodeling Independent Function (RIF), but RIF is functionally very significant. The objective of this grant proposal is to decipher this mysterious novel function. It is known that genes important for T cell activation are mainly regulated by Super Enhancers (SEs). At SEs, diverse transcription regulators attract each other with weak forces and condense into liquid droplets. This process, termed “phase transition”, concentrates and compartmentalizes the transcription regulators, thus driving high-level expression of the target genes within the droplet. Multiple clues suggest that BRG can promote the aforementioned phase transition to activate the SEs and promote Treg activation. Here we plan to test this hypothesis in a comprehensive manner, taking advantage of our unique expertise and resources accumulated in the past and of the latest technological innovations in the field of gene regulation. We expect to obtain ground-breaking results that span the Treg activation and chromatin research fields.