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
Mentions: The rapid kinetics of CIITA silencing suggested that it is a primary response triggered by pre-existing signal-transduction pathways. This was confirmed by the finding that it was not abrogated by the protein-synthesis inhibitor cycloheximide (Figure 2A). Selective inhibitors were used to identify signal-transduction pathways mediating CIITA silencing (Figure 2A). Efficacy of the inhibitors was controlled by qRT-PCR experiments examining the expression of genes induced via the targeted pathways and western-blot experiments examining phosphorylation of signaling intermediates (data not shown). Inhibitors of NF-κB activation, including lactacystine (Figure 2A) and MG-132 (data not shown) had no impact on CIITA silencing. Inhibitors of the c-Jun N-terminal kinase JNK (SP600125), p38 (SB202190) and extracellular signal-regulated kinases ERK (U0126) MAPK pathways also had no impact when added individually. However, CIITA silencing was completely abrogated by blocking both the p38 and ERK pathways (Figure 2A).
Affiliation: Department of Pathology and Immunology, University of Geneva Medical School, CH-1211 Geneva, Switzerland.