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Extensive remodeling of DC function by rapid maturation-induced transcriptional silencing.

Seguín-Estévez Q, Dunand-Sauthier I, Lemeille S, Iseli C, Ibberson M, Ioannidis V, Schmid CD, Rousseau P, Barras E, Geinoz A, Xenarios I, Acha-Orbea H, Reith W - Nucleic Acids Res. (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Immunology, University of Geneva Medical School, CH-1211 Geneva, Switzerland.

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Functional relevance of rapid transcriptional silencing in activated DCs. (A) Schematic summary of signal-transduction pathways and functional consequences triggered by TLR-engagement in DCs: our results define a novel primary silencing pathway that is distinct from known gene induction mechanisms and modulates key processes during DC maturation. The silencing mechanism affects the expression of pivotal proteins (red boxes) implicated in: (B) TLR signaling (MKK6), (C) CLR signaling (SYK), (D) PI3K-Akt signaling (PI3K) and (E) icosanoid biosynthesis (LTA4H, 15-LOX, COX1).
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Figure 7: Functional relevance of rapid transcriptional silencing in activated DCs. (A) Schematic summary of signal-transduction pathways and functional consequences triggered by TLR-engagement in DCs: our results define a novel primary silencing pathway that is distinct from known gene induction mechanisms and modulates key processes during DC maturation. The silencing mechanism affects the expression of pivotal proteins (red boxes) implicated in: (B) TLR signaling (MKK6), (C) CLR signaling (SYK), (D) PI3K-Akt signaling (PI3K) and (E) icosanoid biosynthesis (LTA4H, 15-LOX, COX1).

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.


Extensive remodeling of DC function by rapid maturation-induced transcriptional silencing.

Seguín-Estévez Q, Dunand-Sauthier I, Lemeille S, Iseli C, Ibberson M, Ioannidis V, Schmid CD, Rousseau P, Barras E, Geinoz A, Xenarios I, Acha-Orbea H, Reith W - Nucleic Acids Res. (2014)

Functional relevance of rapid transcriptional silencing in activated DCs. (A) Schematic summary of signal-transduction pathways and functional consequences triggered by TLR-engagement in DCs: our results define a novel primary silencing pathway that is distinct from known gene induction mechanisms and modulates key processes during DC maturation. The silencing mechanism affects the expression of pivotal proteins (red boxes) implicated in: (B) TLR signaling (MKK6), (C) CLR signaling (SYK), (D) PI3K-Akt signaling (PI3K) and (E) icosanoid biosynthesis (LTA4H, 15-LOX, COX1).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
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Figure 7: Functional relevance of rapid transcriptional silencing in activated DCs. (A) Schematic summary of signal-transduction pathways and functional consequences triggered by TLR-engagement in DCs: our results define a novel primary silencing pathway that is distinct from known gene induction mechanisms and modulates key processes during DC maturation. The silencing mechanism affects the expression of pivotal proteins (red boxes) implicated in: (B) TLR signaling (MKK6), (C) CLR signaling (SYK), (D) PI3K-Akt signaling (PI3K) and (E) icosanoid biosynthesis (LTA4H, 15-LOX, COX1).
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.

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Immunology, University of Geneva Medical School, CH-1211 Geneva, Switzerland.

Show MeSH