Genomics

Dataset Information

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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. Overall design: ChIP-seq of DC-SCRIPT (ZNF366) in monocyte-derived DCs from three different donors, stimulated with the TLR ligand R848 for 0, 1 and 24 hours, as well as ChIP-seq for the histone modifications H3K4me3 and H3K27ac in monocyte-derived DCs, stimulated with R848 for 0, 1 and 24 hours.

INSTRUMENT(S): Illumina HiSeq 2000 (Homo sapiens)

SUBMITTER: Simon van Heeringen  

PROVIDER: GSE78923 | GEO | 2018-06-19

REPOSITORIES: GEO

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Publications

Dendritic Cells Actively Limit Interleukin-10 Production Under Inflammatory Conditions <i>via</i> DC-SCRIPT and Dual-Specificity Phosphatase 4.

Søndergaard Jonas Nørskov JN   van Heeringen Simon J SJ   Looman Maaike W G MWG   Tang Chunling C   Triantis Vassilis V   Louche Pauline P   Janssen-Megens Eva M EM   Sieuwerts Anieta M AM   Martens John W M JWM   Logie Colin C   Stunnenberg Hendrik G HG   Ansems Marleen M   Adema Gosse J GJ  

Frontiers in immunology 20180622


Dendritic cell (DC)-based immunotherapy makes use of the DC's ability to direct the adaptive immune response toward activation or inhibition. DCs perform this immune orchestration in part by secretion of selected cytokines. The most potent anti-inflammatory cytokine interleukin-10 (IL-10) is under tight regulation, as it needs to be predominantly expressed during the resolution phase of the immune response. Currently it is not clear whether there is active suppression of IL-10 by DCs at the init  ...[more]

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