Project description:Dendritic-cell (DC) maturation involves substantial remodeling of their gene-expression program. Most research has focused on inducible gene-expression networks promoting the acquisition of new functions, such as cytokine production and enhanced T-cell-stimulatory capacity. In contrast, mechanisms that modulate DC-function by inducing gene silencing remain poorly understood. Here we describe a novel primary epigenetic-silencing response that makes major contributions to the DC-maturation process. The repressed genes function in pivotal processes - including antigen-presentation, extracellular-signal detection, 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 transcription factor in marking genes poised for inducible repression Analysis of PU.1 binding sites in mo-DC
Project description:Dendritic-cell (DC) maturation involves substantial remodeling of their gene-expression program. Most research has focused on inducible gene-expression networks promoting the acquisition of new functions, such as cytokine production and enhanced T-cell-stimulatory capacity. In contrast, mechanisms that modulate DC-function by inducing gene silencing remain poorly understood. Here we describe a novel primary epigenetic-silencing response that makes major contributions to the DC-maturation process. The repressed genes function in pivotal processes - including antigen-presentation, extracellular-signal detection, 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 transcription factor in marking genes poised for inducible repression
Project description:Dendritic-cell (DC) maturation involves substantial remodeling of their gene-expression program. Most research has focused on inducible gene-expression networks promoting the acquisition of new functions, such as cytokine production and enhanced T-cell-stimulatory capacity. In contrast, mechanisms that modulate DC-function by inducing gene silencing remain poorly understood. Here we describe a novel primary epigenetic-silencing response that makes major contributions to the DC-maturation process. The repressed genes function in pivotal processes - including antigen-presentation, extracellular-signal detection, 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 transcription factor in marking genes poised for inducible repression
Project description:Dendritic-cell (DC) maturation involves substantial remodeling of their gene-expression program. Most research has focused on inducible gene-expression networks promoting the acquisition of new functions, such as cytokine production and enhanced T-cell-stimulatory capacity. In contrast, mechanisms that modulate DC-function by inducing gene silencing remain poorly understood. Here we describe a novel primary epigenetic-silencing response that makes major contributions to the DC-maturation process. The repressed genes function in pivotal processes - including antigen-presentation, extracellular-signal detection, 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 transcription factor in marking genes poised for inducible repression
Project description:<p>Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) is a rare and aggressive form of ovarian cancer afflicting young women at a median age of 24 years. SCCOHTs are characterized by loss of protein expression of SWI/SNF chromatin remodeling ATPases SMARCA4 and SMARCA2 through mutation and epigenetic silencing, respectively. This study aims to establish gene expression profiles of this cancer through RNA-Seq of four pathologically confirmed cases of SCCOHT tumors.</p>
Project description:We explored the expression profile during DC differentiation from peripheral monocytes and DC maturation induced by lipopolysaccharide (LPS).
Project description:Rheumatoid Arthritis (RA) is a chronic autoimmune disease which causes degradation of cartilage and bone. It is well appreciated that the pathogenic hallmark of RA is the mass influx of inflammatory cells into the joint. However, the role dendritic cells (DC) may play in this inflammatory milieu is still relatively unexplored. Moreover, the contribution this unique synovial microenvironment has on DC function and maturation is still unknown. Using monocyte-derived DC (MoDC), we established an in vitro model to recapitulate the synovial microenvironment to explore DC maturation. MoDC treated with conditioned media from ex vivo synovial tissue biopsy cultures (ECM) have increased expression of proinflammatory cytokines, chemokines and adhesion molecules. ECM treated DC have increased expression of CD83 and CCR7 and decreased expression of CCR5 and phagocytic capacity, suggestive of heightened DC maturation. ECM induced maturation is concomitant with altered cellular bioenergetics, whereby increased expression of glycolytic genes and increased glucose uptake are observed in ECM treated DC. Collectively, this results in a metabolic shift in DC metabolism in favor of glycolysis. These adaptations are in-part mediated via STAT3 as demonstrated by decreased expression of proinflammatory cytokines and glycolytic genes in ECM treated DC in response to STAT3 inhibition. Finally, to translate this data to a more in vivo clinically relevant setting, we interrogated a previously published synovial DC dataset and identified enhanced expression of glycolytic genes in synovial DC compared to DC in circulation. Collectively, our data suggests that the synovial microenvironment in RA contributes to DC maturation and metabolic reprogramming.