Project description:Stimulus-specific gene expression programs are enabled by enhancers, on which stimulus-regulated transcription factors (SRTFs) can land in a cell type- and stimulus-dependent manner. In this study, we identified the key features of enhancers that mediate differential responses to Toll-like receptor (TLR)-stimulation. We characterized the TLR3- and TLR9-induced programs and enhancers in CD8+ dendritic cells.The relevance of these features has been confirmed via machine learning application and by mapping SRTF-binding.
Project description:Stimulus-specific gene expression programs are enabled by enhancers, on which stimulus-regulated transcription factors (SRTFs) can land in a cell type- and stimulus-dependent manner. In this study, we identified the key features of enhancers that mediate differential responses to Toll-like receptor (TLR)-stimulation. We characterized the TLR3- and TLR9-induced programs and enhancers in CD8+ dendritic cells.The relevance of these features has been confirmed via machine learning application and by mapping SRTF-binding.
Project description:Stimulus-specific gene expression programs are enabled by enhancers, on which stimulus-regulated transcription factors (SRTFs) can land in a cell type- and stimulus-dependent manner. In this study, we identified the key features of enhancers that mediate differential responses to Toll-like receptor (TLR)-stimulation. We characterized the TLR3- and TLR9-induced programs and enhancers in CD8+ dendritic cells.The relevance of these features has been confirmed via machine learning application and by mapping SRTF-binding.
Project description:This SuperSeries is composed of the following subset Series: GSE32709: DNA methylation regulates lineage-specifying genes in the human vascular system [expression array]. GSE34486: DNA methylation regulates lineage-specifying genes in the human vascular system [methylation array]. Refer to individual Series
Project description:Activation of interferon-stimulated gene (ISG) responses is critical for control of viral infection. We recently identified that stimulation of the NLRP3 inflammasome and mobilization of the inflammatory cytokine IL-1β act as critical host restrictive pathways against West Nile virus (WNV) in a mechanism dependent on the regulation of ISGs. In order to define the mechanism by which IL-1β regulates these antiviral immune programs, we utilized global transcriptome analysis in myeloid cells, known targets of WNV replication to define gene signatures required for IL-1β driven antiviral responses. Surprisingly, we found IL-1β dependent activation of interferon-beta (IFN-β) and ISGs at late times following IL-1β treatment. Expression of these antiviral innate immune genes was found to be dependent on activation of IRF3 and appears to reflect a general shift in IL-1β signaling from an inflammatory response early following treatment to an anti-inflammatory type-I IFN mediated response at later times post-treatment. These data demonstrate that inflammatory and antiviral signals integrate to control viral infection. Strategies to co-opt these cytokine activated antiviral signatures can act as novel targeted therapeutic strategies tailored specifically to individual pathogens.
Project description:The Mediator complex routes signals from DNA-binding transcription factors to RNA polymerase (Pol) II. Despite its pivotal position, mechanistic understanding of Mediator in human cells remains incomplete. Here, we quantified Mediator-controlled Pol II kinetics by coupling rapid subunit degradation with orthogonal experimental readouts. Consistent with a model of condensate-driven transcription initiation, large clusters of hypo-phosphorylated Pol II rapidly disassembled upon Mediator degradation. This was accompanied by a selective and pronounced disruption of cell type-specifying transcriptional circuits, whose constituent genes featured exceptionally high rates of Pol II turnover. Remarkably, transcriptional output of most other genes was largely unaffected by acute Mediator ablation. Maintenance of transcriptional activity at these genes was linked to an unexpected, CDK9-dependent compensatory feedback loop that elevated Pol II pause release rates genome-wide. Collectively, our work positions human Mediator as a globally acting coactivator that selectively safeguards the functionality of cell type-specifying transcriptional networks.