Super-enhancer-driven transcriptional program contributes to psoriasis pathogenesis

Summary: Abstract Body: Background: Super-enhancers (SEs) are compound regulatory elements that control expression of key cell identity genes. Transcription factor FOSL1 plays a crucial role in cell differentiation, response to environmental stresses, and tumorigenesis. Whether FOSL1 contributes to psoriasis pathogenesis through activating psoriasis related enhancers remain unclear. Methods: RNA-seq and H3K27ac CUT&tag were used to construct enhancers map in psoriasis. CRISPR-based technologies were used to delete SEs. IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α (M5 cytokines) stimulated keratinocytes and Imiquimod induced mice were used as cell and animal models of psoriasis. Results: Global H3K27ac modification levels were elevated in psoriasis lesions and M5-stimulated HaCaT cells, identifying 468 and 254 differentially active enhancers in lesions and cell models, respectively. Pathway enrichment showed that genes regulated by active enhancers were involved in inflammatory pathways. SE inhibitor JQ-1 improved IMQ-induced psoriasis-like dermatitis in mice and inhibited proliferation and promoted apoptosis in M5-stimulated HaCaT cells. Moreover, we identified a SE in IL1 family gene cluster according to the genes expression change and H3K27ac enrichment. IL1-SE knockout in HaCaT cells lead to downregulation of IL1A, IL1B, IL36G, and IL36RN mRNA expression. Motif analysis showed significant enrichment of the transcription factor FOSL1 in SE regions, which was highly expressed in keratinocytes of psoriasis lesions. Combining FOSL1 and H3K27ac CUT&tag data, we found co-localization of FOSL1 and H3K27ac across the genome, and knockdown of FOSL1 reduced H3K27ac occupancy and SE activity. Mechanistically, the upregulation of FOSL1 promotes phase separation, facilitating the aggregation of the EP300 transcriptional complex in IL1-SE. Conclusion: Aberrant upregulation of FOSL1 forms phase-separated liquid condensates with EP300, activating SEs and promoting the transcription of pathogenic genes in keratinocyte of psoriasis. Ming Zhao¹, Yueqi Qiu¹ 1. Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nan Jing, China. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics