Project description:T cell prolymphocytic leukemia (T-PLL) is mostly characterized by aberrant expansion of small to medium sized pro-lymphocytes with a mature post-thymic phenotype, high aggressiveness of the disease and poor prognosis. However, T-PLL is more heterogeneous with a wide-range of clinical, morphological, and molecular features, which occasionally impedes the diagnosis. We hypothesized that T-PLL consists of phenotypic and genotypic subgroups that may explain the heterogeneity of the disease. We found that T-PLL does not show a clear skewing in T cell receptor alpha (TRA), TRB gene usage and CDR3 stereotypy. In addition, multi-dimensional immuno-phenotyping and gene expression profiling did not reveal clear T-PLL subgroups. However, based on miRNA expression profiles, T-PLL samples did clearly cluster in subgroups. We identified 35 miRNAs that were aberrantly expressed in T-PLL with miR-200c/141 as the most differentially expressed cluster. High miR-200c/141 expression was significantly correlated with increased white blood cell counts and poor survival. Furthermore, we found that overexpression of miR-200c/141 in T-PLL correlated with downregulation of their targets ZEB2 and TGFβR3, indicating that the TGFβ pathway is affected. Our results thus highlight the emerging role for aberrantly expressed oncogenic miRNAs in T-PLL, thereby paving the way for new therapeutic targets in this disease.
Project description:Previous research has linked perceived social isolation (loneliness) to reduced antiviral immunity, but the immunologic effects of the objective social isolation imposed by pandemic “shelter in place” (SIP) policies is unknown. We assessed the immunologic impact of SIP by relocating 21 adult male rhesus macaques from 2000 sq-m field cage communities of 70-132 other macaques to 2 wks of individual housing in indoor shelters. SIP was associated with down-regulation of Type I interferon (IFN) antiviral gene expression. This effect emerged within the first 48 hrs of SIP, persisted for at least 2 wks, and abated within 4 wks of return to social housing. A subsequent round of SIP in the presence of a novel juvenile macaque abrogated this effect. These results identify a significant adverse effect of SIP social isolation on antiviral immune regulation in circulating immune cells and they suggest a potential behavioral strategy for ameliorating such effects by promoting pro-social engagement during SIP.
Project description:T-cell prolymphocytic leukemia (T-PLL) is a rare disease with rapid clinical course. Whole-exome and whole-genome sequencing have identified structural alterations in T-PLL, including inversion, translocation and copy number variation. Epigenetic alterations are the hallmark of many cancers. However, genome-wide epigenomic profiles have not been reported in T-PLL. In this study, we generated genome-wide maps of regulatory regions in both T-PLL patients and healthy individuals using H3K4me3 and H3K27ac ChIP-seq. We revealed a global alteration of both promoter and enhancer landscape in T-PLL, which supported the role of epigenetic regulation in transcriptional dysregulation of oncogenes and genes involved in DNA damage response and T-cell activation.
Project description:Bioavailability of electron acceptors is probably the most limiting factor in the restoration of anoxic, contaminated environments. The oxidation of contaminants such as aromatic hydrocarbons, particularly in aquifers, often depends on the reduction of ferric iron or sulphate. We have previously detected a highly active fringe zone beneath a toluene plume at a tar-oil contaminated aquifer in Germany, where a specialized community of contaminant degraders co-dominated by Desulfobulbaceae and Geobacteraceae had established. Although on-site geochemistry links degradation to sulphidogenic processes, dominating catabolic (benzylsuccinate synthase alpha-subunit, bssA) genes detected in situ appeared more related to those of Geobacter spp. Therefore, a stable isotope probing (SIP) incubation of sediment samples with 13C7-toluene and comparative electron acceptor amendment was performed. We introduce pyrosequencing of templates from SIP microcosms as a powerful new strategy in SIP gradient interpretation (Pyro-SIP). Our results reveal the central role of Desulfobulbaceae for sulphidogenic toluene degradation in situ, and affiliate the detected bssA genes to this lineage. This, and the absence of 13C-labelled DNA of Geobacter spp. in SIP gradients preclude their relevance as toluene degraders in situ. In contrast, Betaproteobacteria related to Georgfuchsia spp. became labelled under iron-reducing conditions. Furthermore, secondary toluene degraders belonging to the Peptococcaceae detected in both treatments suggest the possibility of functional redundancy amongst anaerobic toluene degraders on site.
Project description:We developed an adaptation to Split-Pool Recognition of Interactions by Tag Extension (SPRITE) called SPRITE-immunoprecipitation (SIP), which enables us to map genome-wide higher-order interactions that are coupled with the protein of interest. In this study we generated SIP data fo H3K4me3 and pan-promoter mark. We generated SIP maps in two mammalian cell types – mouse embryonic stem cells (mES) and mouse bone marrow derived dendritic cells.
Project description:T-cell prolymphocytic leukemina (T-PLL) is an agressive lymphoma derived from mature T-cells, which is in most cases characterized by the presence of an inv(14)(q11q32) and a characteristic pattern of secondary chromosomal abberations. We used microarrays to compare the transcriptomes of eight immunomagnetically purified CD3+ normal donor derived peripheral blood cells with five highly purified inv(14)-positive T-PLL blood samples. Experiment Overall Design: Purified T-PLL cells and normal T-cells were analyzed on microarrays to identify differentially expressed genes. High-resolution copy number determination using SNP-chip technology and FISH in twelve inv(14)-positive T-PLL showed that differentially expressed genes clustered significantly in regions affectd by recurrent chromosomal imbalances.