Research

Project 1: Molecular mechanisms of Aire condensates in T cell tolerance

Autoimmune regulator (Aire) is an SP family member that is critical for establishing central T cell tolerance. Aire drives the expression of thousands of tissue-specific antigens (TSAs) in medullary thymic epithelial cells (mTECs), enabling self-reactive T cells to undergo negative selection or develop into regulatory T cells. The importance of Aire in maintaining self-tolerance is highlighted by mutations in AIRE that cause the rare disorder Autoimmune Polyendocrine Syndrome Type 1 (APS-1). 

Aire carries out its unique function in T cell tolerance by activating an exceptionally broad gene expression program. Although each mTEC expresses only a subset of TSAs, the mTEC population as a whole covers nearly 90% of all protein-coding genes! Aire is also unusual in that it forms large nuclear condensates. While our previous work demonstrated that Aire condensates are active sites of transcription, the precise role of Aire condensates in upregulating a vast set of genes still remains unclear. Our project goals are:

I. Investigate Aire condensate dynamics. We are elucidating how Aire interacts with chromatin and transcriptional co-activators to initiate condensate formation by applying live-cell imaging approaches to capture the underlying dynamics..

II. Characterize autoimmune disease-associated mutations. Some APS-1 mutants still form condensates, yet their mechanism of pathogenesis remains a mystery. We seek to understand how these AIRE mutations can alter Aire condensate formation, dynamics, and function.

III. Elucidate Aire condensate turnover. mTECs that used to express Aire (“post-Aire” mTECs) continue to express and present TSAs even after Aire expression declines. This suggests that Aire condensates are turned over, and that this process is functionally significant for maintaining antigen presentation. We are investigating how Aire condensates are disassembled and how their dissolution impacts transcriptional programs in T cell tolerance.  

Project 2: Sp140 in immune homeostasis and pathogenesis

Sp140, a member of the SP protein family, assembles into nuclear condensates, but the function of these assemblies remains unknown. Sp140 is expressed specifically in immune cells, which suggests that it is highly specialized for immune regulation rather than acting as a general transcriptional regulator. Previous studies have demonstrated that Sp140 functions as a transcriptional repressor with roles in shaping immune cell fate and mediating antiviral signaling. Sp140 dysfunction has been linked to autoimmune and inflammatory diseases including multiple sclerosis, inflammatory bowel disease, and Crohn’s disease. Building on insights from our Aire research, we are investigating the molecular mechanisms of Sp140 condensates and elucidating how their misregulation may contribute to immune disease. Our lab seeks to:

I. Determine mechanisms of Sp140 condensate formation. Sp140 contains a filament-forming CARD domain and chromatin-interacting modules, but how these features contribute to condensate assembly and regulation is unknown. Recent studies suggest that Sp140 can target specific genomic loci, raising the possibility that condensate formation and chromatin targeting are mechanistically linked. We are exploring how Sp140 domains influence condensate formation, nuclear localization, and regulation of gene expression programs.

II. Investigate Sp140 condensates in transcriptional repression. Only one SP member condensate has been mechanistically shown to promote transcriptional activation. By contrast, Sp140 functions as a transcriptional repressor, but how its condensates silence genes remains unknown. We are investigating how Sp140 mediates repression once assembled, focusing on potential mechanisms such as regulatory factor recruitment or sequestration.

III. Elucidate mechanisms of Sp140 dysfunction. We are characterizing the effects of disease-associated SP140 variants on condensate formation and function. In parallel, we are probing how pharmacological perturbation alters Sp140 condensates and transcriptional repression.