Extensive remodeling of DC function by rapid maturation-induced transcriptional silencing.
Bottom Line: This silencing response is a rapid primary event distinct from repression mechanisms known to operate at later stages of DC maturation.The repressed genes function in pivotal processes--including antigen-presentation, extracellular signal detection, intracellular signal transduction and lipid-mediator biosynthesis--underscoring the central contribution of the silencing mechanism to rapid reshaping of DC function.Interestingly, promoters of the repressed genes exhibit a surprisingly high frequency of PU.1-occupied sites, suggesting a novel role for this lineage-specific transcription factor in marking genes poised for inducible repression.
Affiliation: Department of Pathology and Immunology, University of Geneva Medical School, CH-1211 Geneva, Switzerland.Show MeSH
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Mentions: CIITA mRNA abundance is decreased during DC maturation (19,21,28). To clarify the mechanism involved, CIITA-silencing was investigated in human monocyte-derived DCs (Mo-DCs). CIITA-silencing was induced by diverse stimuli—including LPS, tumor necrosis factor (TNFα), peptidoglycan (PGN), Pam3CysSerLys4 (PAM), polyinosinic-polycytidylic acid (pIC) and flagellin (Flag)—indicating that it is a general feature of Mo-DC maturation (Figure 1A). Time-course experiments demonstrated that LPS-induced down-regulation of CIITA mRNA was detectable by 1 h and reached baseline levels by 2 h (Figure 1B). This decrease preceded the induction of IL12B (Figure 1B) and IL6 (data not shown) mRNAs. LPS-concentrations as low as 0.25 ng/ml were sufficient to trigger CIITA-silencing, whereas higher concentrations were required for optimal induction of IL12B (Figure 1C) and IL6 (data not shown) mRNAs. Quantification of chromatin-bound nascent transcripts demonstrated that LPS-induced down-regulation of CIITA mRNA resulted from an arrest in transcription that was evident by 15 min and almost complete after 1 h (Figure 1D). Quantitative chromatin-immunoprecipitation (qChIP) experiments revealed a rapid LPS-induced disengagement of RNA-polymerase-II (pol-II) at the DC-specific promoter (pI) of CIITA (Figure 1E).
Affiliation: Department of Pathology and Immunology, University of Geneva Medical School, CH-1211 Geneva, Switzerland.