Runx1 and RORγt Cooperate to Upregulate IL-22 Expression in Th Cells through Its Distal Enhancer
| Autor: | Hironobu Asao, Masayuki Sekimata, Ken Iseki, Akemi Araki, Akiko Murakami-Sekimata, Daiki Yoshida |
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| Rok vydání: | 2019 |
| Předmět: |
Cellular differentiation
Amino Acid Motifs Immunology Histone H4 Mice 03 medical and health sciences 0302 clinical medicine RAR-related orphan receptor gamma Animals Immunology and Allergy RNA Small Interfering Enhancer Transcription factor Cells Cultured Conserved Sequence Tissue homeostasis Orphan receptor Mice Inbred BALB C Gene knockdown Chemistry Interleukins Cell Differentiation Receptors Interleukin T-Lymphocytes Helper-Inducer Nuclear Receptor Subfamily 1 Group F Member 3 Up-Regulation Cell biology Mice Inbred C57BL Enhancer Elements Genetic Core Binding Factor Alpha 2 Subunit Mutation Protein Binding 030215 immunology |
| Zdroj: | The Journal of Immunology. 202:3198-3210 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1800672 |
| Popis: | IL-22 is a cytokine that plays a pivotal role in regulating tissue homeostasis at barrier surfaces and is produced by activated CD4+ Th cells. Currently, the molecular mechanisms regulating Il22 gene expression are still unclear. In this study, we have identified a crucial cis-regulatory element located 32 kb upstream of the mouse Il22 promoter, termed conserved noncoding sequence (CNS)–32. We demonstrated that CNS-32 acts as an enhancer in reporter assays and contains binding motifs for Runt-related transcription factor (Runx)1 and retinoic acid–related orphan receptor γt (RORγt). Mutation of these motifs significantly abrogated the reporter activity, suggesting a role for both factors in the control of enhancer-mediated Il22 expression. Runx1 and RORγt occupancy and elevated histone H4 acetylation at CNS-32 were evident, as naive T cells differentiated into IL-22–producing Th22 cells. Overexpression of Runx1 promoted IL-22 production by inducing RORγt and IL-23 receptor, all critical to Th22 cell induction. Although Runx1 alone enhanced IL-22 production in Th22 cells, it was further enhanced in the presence of RORγt. Conversely, short hairpin RNA–mediated knockdown of core-binding factor β, a cofactor essential for Runx1 activity, was effective in limiting IL-22 production. Collectively, our results suggest that IL-22 production is controlled by a regulatory circuit in which Runx1 induces RORγt and then partners with RORγt to direct Il22 expression through their targeting of the Il22 enhancer. |
| Databáze: | OpenAIRE |
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