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: Gene-ontology analyses demonstrated that genes subjected to silencing are strongly enriched in immune-system processes, including numerous genes implicated in DC function (Figure 3B and Supplementary Table S3). The most relevant processes include Ag uptake and presentation, extracellular-signal detection, signal transduction, lipid metabolism, cell migration and cytokine production (Figure 7 and Supplementary Table S3, see ‘Discussion’ section). Although down-regulated expression during DC-maturation was reported for certain genes, such as CIITA, MARCH1 and CD36 (20,21), for the majority this has not been documented. Rapid epigenetic silencing is thus a newly identified mechanism that concerns numerous functionally relevant genes and makes a major contribution to transcriptional reprogramming of DCs at an early stage of the maturation process.
Affiliation: Department of Pathology and Immunology, University of Geneva Medical School, CH-1211 Geneva, Switzerland.