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DC-SCRIPT binds GA-rich enhancers to control MAPK-signaling and IL-10 production in human dendritic cells

ABSTRACT: Dendritic cells (DCs) uniquely direct the adaptive immune response towards activation or inhibition, yet little is known how these opposite programs are regulated at the transcriptional level. Here we applied genome-wide approaches to delineate the molecular function of DC-Specific transCRIPT (DC-SCRIPT/ZNF366), an 11 Zn finger-containing transcription factor potentiating DC-function by limiting IL-10 production. Transcriptome analysis identified DC-SCRIPT to affect expression of genes involved in MAPK signaling, and ChIP-Seq analysis showed binding of DC-SCRIPT to GA-rich enhancers nearby genes encoding MAPK Dual-Specificity Phosphatases (DUSPs). Functional studies demonstrated that DC-SCRIPT-knockdown DCs express much less DUSP4 and exhibit increased phosphorylation of all the three major MAPKs (ERK, JNK and p38). Enhanced ERK signaling in DC-SCRIPT-knockdown DCs led to higher production of the immune-inhibitory cytokine IL-10, which could be reverted by DUSP4 overexpression. These results delineate the molecular mechanism DC-SCRIPT employs to limit IL-10 production in DCs, thereby fine-tuning these professional antigen-presenting cells towards immune activation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE78923 | GEO | 2018/06/19

REPOSITORIES: GEO

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