Sharma, Priyanka

Abstract Transcriptional condensates (TCs) are dynamic, membrane-less assemblies of proteins and nucleic acids that form at specific genomic loci to control gene expression. The primary drivers of TC formation and function are long stretches of polypeptide chains that lack well-defined tertiary structure, known as the intrinsically disordered regions (IDRs) of Transcription Factors (TFs). However, the role of well-structured domains such as the DNA-binding domain (DBD) in condensate formation and downstream regulation remains poorly understood. Here, we investigated whether the DBD of the Progesterone Receptor (PR), a model TF regulated by hormone binding, contributes to the formation of PR TCs. By combining Single Particle Tracking (SPT) with deep-learning-based single-trajectory analysis, we demonstrated that both the IDR and the DBD are required for the formation of PR condensates. Furthermore, transcriptomic analysis showed that mutations of either of the two domains result in the expression of a distinct set of genes, with functional assays corroborating these findings and linking domain-specific transcription to differential effects on cell proliferation and migration. Together, our results show that domains beyond IDRs also play a role in TC formation and function and uncover domain-specific regulation of transcriptional and oncogenic programs.

Abstract Cutaneous T-cell lymphoma (CTCL) is a rare malignancy of skin-resident T cells characterized by an aberrant cytokine profile, notably elevated Interleukin-17A (IL-17A) levels. However, the functional importance of IL-17A dysregulation in the CTCL pathogenesis remains poorly understood. Our analysis revealed increased IL-17A receptor (IL-17RA) expression in CTCL patient samples, supporting the importance of IL-17A signaling in CTCL progression. Proteomic and metabolomic profiling of IL-17A-treated malignant T cells revealed mitochondrial electron transport chain (ETC) complex I as a key downstream target of IL-17A signaling. Furthermore, we confirmed the elevated expression of ETC complex I in CTCL patient samples compared to healthy control T cells, hence highlighting the clinical relevance of the IL-17A signaling-ETC complex 1 axis. Altogether, our data unveil the function of IL-17A signaling in the metabolic axis in CTCL progression, which could be useful for developing advanced therapeutic strategies. Significance statement: We uncover an IL-17A-induced electron transport chain (ETC) complex I pro-tumorigenic circuit and provide proof of concept evidence that ETC complex I can be targeted to combat the challenges posed by Cutaneous T-cell Lymphoma aggressiveness.