1. Academic Validation
  2. Mechanism for controlled assembly of transcriptional condensates by Aire

Mechanism for controlled assembly of transcriptional condensates by Aire

  • Nat Immunol. 2024 Sep;25(9):1580-1592. doi: 10.1038/s41590-024-01922-w.
Yu-San Huoh # 1 2 Qianxia Zhang # 1 2 Ricarda Törner 2 3 Sylvan C Baca 4 Haribabu Arthanari 2 3 Sun Hur 5 6
Affiliations

Affiliations

  • 1 Howard Hughes Medical Institute and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 5 Howard Hughes Medical Institute and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA. Sun.Hur@crystal.harvard.edu.
  • 6 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. Sun.Hur@crystal.harvard.edu.
  • # Contributed equally.
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.

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