Postdoctoral Fellow Ohio State Univ., United States
Disclosure(s):
Leone Hopkins, DVM: No financial relationships to disclose
Introduction/Rationale: IL22 is a type III cytokine produced by innate and adaptive lymphocytes that is essential for maintaining tissue homeostasis and establishing a defense against extracellular pathogens. Dysregulation of IL22 contributes to the development of immune-mediated diseases such as psoriasis.
Methods: We identified two conserved enhancer elements (E22-1 and E22-2) for Il22 by a CRISPR interference (CRISPRi) screen. We additionally identified a superenhancer for Il22 (SE22) using H2K27ac chromatin immunoprecipitation sequencing (ChIP-Seq) of human tonsillar ILC3s, which is also conserved in mouse.
Results: Knockout mice for SE22 or E22-1 resulted in partial loss of IL-22 expression in ILC3s as well as αβ T, iNKT, and γδ T cells. In contrast, deletion of E22-2 impaired IL-22 expression only in ILC3s. We demonstrate that the enhancer elements are bound by the RUNX family and RORC transcription factors in a site dependent manner resulting in cell type specific control of IL22 expression in ILC3s by E22-2. We further demonstrate that the partial loss of IL22 in each of the knockout strains protects from development of imiquimod induced psoriasis through a decrease in Il22 but not Il17a or Il17f.
Conclusion: Further characterization of cis-regulatory elements of Il22 may provide key targets for epigenetic therapy to treat autoimmune disease.
