Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
Nat Commun. 2018 Nov 15;9(1):4803. doi: 10.1038/s41467-018-07202-0.
Cytokine genes are regulated by multiple regulatory elements that confer tissue-specific and activation-dependent expression. The cis-regulatory elements of the gene encoding IL-9, a cytokine that promotes allergy, autoimmune inflammation and tumor immunity, have not been defined. Here we identify an enhancer (CNS-25) upstream of the Il9 gene that binds most transcription factors (TFs) that promote Il9 gene expression. Deletion of the enhancer in the mouse germline alters transcription factor binding to the remaining Il9 regulatory elements, and results in diminished IL-9 production in multiple cell types including Th9 cells, and attenuates IL-9-dependent immune responses. Moreover, deletion of the homologous enhancer (CNS-18) in primary human Th9 cultures results in significant decrease of IL-9 production. Thus, Il9 CNS-25/IL9 CNS-18 is a critical and conserved regulatory element for IL-9 production.
细胞因子基因受多种调节元件调控，赋予组织特异性和激活依赖性表达。编码白细胞介素 9（IL-9）的基因的顺式调节元件尚未确定，IL-9 是一种促进过敏、自身免疫炎症和肿瘤免疫的细胞因子。在这里，我们鉴定了 Il9 基因上游的一个增强子（CNS-25），它结合了大多数促进 Il9 基因表达的转录因子（TFs）。在小鼠种系中删除增强子会改变转录因子与剩余 Il9 调节元件的结合，导致包括 Th9 细胞在内的多种细胞类型中 IL-9 的产生减少，并减弱 IL-9 依赖性免疫反应。此外，在原代人 Th9 培养物中删除同源增强子（CNS-18）会导致 IL-9 的产生显著减少。因此，Il9 CNS-25/IL9 CNS-18 是 IL-9 产生的关键和保守的调节元件。
