Transcription factor ZNF750 recruits histone demethylase KDM1A to manage immune response

Summary: Abstract Body: The epidermis provides a physical barrier as well as manages immune responses in the skin. However, how keratinocytes engage in immune sensing or mediates immune tolerance is unclear. Here we uncover that ZNF750, a transcription factor specific to differentiated keratinocytes, recruits the epigenetic regulator KDM1A to silence genes coding for pattern recognition receptors (PRRs). We show that differentiated keratinocytes expressing ZNF750 are resistant to Poly IC stimulation, while undifferentiated cells which don’t express ZNF750 generate a robust inflammatory response. Knockdown of ZNF750 in differentiated keratinocytes leads to an enhanced inflammatory response including increased pro-inflammatory cytokines, interferon response genes and PRRs. Epidermis-specific Zfp750 knockout mice exhibit severe and persistent skin inflammation with neutrophil infiltration and psoriasis-like features following UVB-induced damage. In an Imiquimod-induced psoriasis model, Zfp750 knockout skin are also more inflamed with increased neutrophils and Th17 cells in the skin-draining lymph nodes. ZNF750 ChIP-Seq reveal that it binds and inhibits the expression of TLR3, IFIH1, DDX58 and inflammatory genes through its canonical DNA binding motif. Silencing TLR3 in ZNF750 knockdown cells reduces hyperinflammation to Poly IC. Similarly, Zfp750 and Tlr3 double-knockout mice dampen the cutaneous inflammatory response after UVB irradiation. We further determine that ZNF750 recruits KDM1A to repress inflammatory genes by using KDM1A ChIP-Seq and Co-immunoprecipitation. KDM1A siRNA silencing in differentiated keratinocytes also promotes a strong inflammatory response upon PolyIC stimulation and this can be rescued by simultaneously silencing with TLR3. Epidermis-specific Kdm1a mice exhibited similar phenotype as Zfp750 with a hyperinflammatory response following UVB or imiquimod treatment. Overall, we reveal that ZNF750-KDM1A axis is critical for dampening cutaneous inflammatory responses. Ye Liu¹, George Sen¹ 1. Dermatology, University of California San Diego, La Jolla, CA, United States. Innate Immunity, Microbiology, and Microbiome