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: Examinations of selected genes indicated that nascent-transcript sequencing allows reliable quantification of transcription rates at genes that are silenced or induced in 1 h-LPS-treated Mo-DCs, including protein-coding and microRNA genes (Figure 4B, C and Supplementary Figure S4C). Global analyses indicated that markedly more changes in expression were evident at the primary-transcript level than at that of mRNA-abundance (Figure 5A and Supplementary Table S1). Significantly more genes were down-regulated at the nascent transcript level than at the mRNA level (Figure 5B and Supplementary Table S1), suggesting that most reductions in transcription rate induced by 1 h of LPS stimulation do not yet have a major impact on mRNA abundance. These results demonstrate that assessing gene silencing by nascent-transcript sequencing is significantly more reliable and has strongly improved temporal resolution compared to mRNA-profiling.
Affiliation: Department of Pathology and Immunology, University of Geneva Medical School, CH-1211 Geneva, Switzerland.