| First Author | Sekimata M | Year | 2019 |
| Journal | J Immunol | Volume | 202 |
| Issue | 11 | Pages | 3198-3210 |
| PubMed ID | 31028121 | Mgi Jnum | J:390769 |
| Mgi Id | MGI:6306253 | Doi | 10.4049/jimmunol.1800672 |
| Citation | Sekimata M, et al. (2019) Runx1 and RORgammat Cooperate to Upregulate IL-22 Expression in Th Cells through Its Distal Enhancer. J Immunol 202(11):3198-3210 |
| abstractText | 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 gammat (RORgammat). 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 RORgammat 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 RORgammat 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 RORgammat. Conversely, short hairpin RNA-mediated knockdown of core-binding factor beta, 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 RORgammat and then partners with RORgammat to direct Il22 expression through their targeting of the Il22 enhancer. |
