A new mode of transcriptional hub assembly by autoimmune regulator Aire

Transcriptional hubs have emerged as critical structural components in gene expression and regulation. Studies on hub assembly have primarily focused on the concept of phase separation of disordered regions within transcriptional regulators (TRs). We here introduce an unexplored mode of hub assembly by investigating the Autoimmune regulator (Aire), an indispensable TR in immune homeostasis distinguished by its unique capacity to form homopolymers. We demonstrate that Aire forms active transcriptional hubs connecting disparate inter-chromosomal genomic loci, and that this hub assembly relies on both Aire's polymerizing domain CARD and the transcriptional activation domain (TAD). In a departure from the conventional TAD functions, Aire's TAD orchestrates site-specific hub assembly by coupling CARD polymerization with genomic targeting. Through direct interactions with the co-activators CBP/p300, Aire TAD guides Aire to genomic loci enriched with CBP/p300, where CARD polymerization is initiated. To avert unwanted CARD polymerization at inappropriate sites, Aire employs its chromatin reader domain PHD1 to disperse Aire outside of its target sites and confine Aire polymerization to CBP/p300-rich loci. Our work thus reveals previously unrecognized mechanism by which a TAD and a chromatin reader domain collaborate to discern genomic loci and facilitate TR polymerization, unveiling a multi-layered assembly process for transcriptional hubs. ### Competing Interest Statement The authors have declared no competing interest.