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: PU.1 is the most strongly expressed ETS-family member in Mo-DCs (Figure 6A and Supplementary Table S2). ChIP-sequencing experiments were performed to map PU.1 binding in Mo-DCs. The distribution of PU.1-bound sites was compared between the promoter regions of genes that are deacetylated-silenced, induced or unchanged in their expression in response to LPS (Figure 6B). The promoters of all human genes were used as baseline. PU.1-occupied sites were more frequent relative to baseline in all three subsets, distributed symmetrically upstream and downstream of the TSS, and enriched most strongly near the TSS. Surprisingly, PU.1-bound sites were most frequent in deacetylated-silenced genes. Binding was not affected by LPS treatment at most positions, indicating that silencing is not due to PU.1-disengagement (Supplementary Figure S5).
Affiliation: Department of Pathology and Immunology, University of Geneva Medical School, CH-1211 Geneva, Switzerland.