Abstract
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.
Highlights
Cytokine genes are regulated by multiple regulatory elements that confer tissue-specific and activation-dependent expression
We show that an element 25 kb upstream from the Il9 gene has enhancer characteristics defined by histone modifications, transcription factor binding, and reporter assays
To begin to define additional regulatory elements of the Il9 gene, we performed chromatin immunoprecipitation and high-throughput sequencing (ChIPseq) analysis of Th9 cells using Abs to the transcriptional coactivator p300, which is documented to be associated with enhancer elements[32,33]
Summary
Cytokine genes are regulated by multiple regulatory elements that confer tissue-specific and activation-dependent expression. With the exception of PU.[1], which bound predominantly to the promoter region, all of the transcription factors showed binding peaks at CNS-25 in Th9 cells (Fig. 2a). To determine if the deletion of CNS-25 affected IL9 production, we differentiated naive CD4+ T cells from WT and Il9ΔCNS-25 mice.
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