Dynamic role of chromatin remodeler in the regulation of RORγt-mediated type 3 skin inflammation

Summary: Abstract Body: The transcription factor RORγt is the master regulator of IL-17 production in T cells. For transcription factors to function optimally, epigenetic modification and chromatin repositioning by chromatin remodelers are essential. Nevertheless, the epigenetic regulatory network involving RORγt in T cells during psoriasis-like skin inflammation remains largely undefined. In this study, we conducted a genome-wide chromatin immunoprecipitation analysis under in vitro Th17 cell differentiation conditions. The results revealed that the chromatin remodeler Chd4 is positioned around RORγt binding regions on DNA, including IL-17A and IL-17F, thereby maintaining these regions in a highly epigenetically active state. Chd4 and RORγt were also found in close proximity in γδT cells. We then generated γδT cell-specific conditional knockout (Chd4-gdTcKO) mice and induced type 3 skin inflammation with imiquimod application. Compared to wild-type (WT) mice, Chd4-gdTcKO mice exhibited significantly reduced ear swelling (WT: 263.8±27.5 μm, Chd4-gdTcKO: 215.6±19.4 μm, P<0.0001) and decreased expression of IL-17A and IL-17F. In vitro, deficiency of Chd4 in gdT cells resulted in decreased production of IL-17A and IL-17F when activated with CD3/CD28 and IL-23/IL-6/IL-1/TGFb. Furthermore, single-cell analysis of cells infiltrating the ears identified a unique γδ T cell subset by the absence of Chd4. These results demonstrate that Chd4-mediated chromatin remodeling regulates the DNA accessibility and binding of the transcription factor RORγt both physically and functionally, emphasizing the crucial role of Chd4 in IL-17A/IL-17F production in the skin and the development of psoriasis. Sayaka Shibata¹, Yukiko Ito¹, Yuka Mizuno¹, Lixin Li¹, Toyoki Yamamoto¹, Hiroyuki Takaba², Shinichi Sato¹ 1. Dermatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 2. Immunology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Innate Immunity, Microbiology, and Microbiome