Project description:JC polyomavirus (JCPyV) established a persistent infection, but BK polyomavirus (BKPyV) killed the cells in 15 days. To identify the cellular factors responsible for controlling JCPyV infection and promoting viral persistence, we profiled the transcriptomes of JCPyV- and BKPyV-infected cells at several time points postinfection. We found that interferon-stimulated genes (ISGs) were only activated in the JCPyV and not in the BKPyV-infected cells.
Project description:BK polyomavirus (BKPyV) is a small DNA virus that establishes a life-long persistent infection in the urinary tract of most people. BKPyV is known to cause severe morbidity in renal transplant recipients and can lead to graft rejection. The simple 5.2 kilobase pair dsDNA genome expresses just seven known proteins, thus it relies heavily on host machinery to replicate. How the host proteome changes over the course of infection is key to understanding this host:virus interplay. Here for the first time quantitative temporal viromics has been used to quantify global changes in >9,000 host proteins in two types of primary human epithelial cell throughout 72 hours of BKPyV infection. These data demonstrate the importance both of cell cycle progression and pseudo-G2 arrest in effective BKPyV replication, along with a surprising lack of innate immune response throughout the whole virus replication cycle. BKPyV thus evades pathogen recognition to prevent activation of innate immune responses in a sophisticated manner.
Project description:mRNAseq data for differentiated and mitotically-quiescent Normal Human Urothelial (NHU) cells at 14 days post infection (dpi) with BKPyV
Project description:Here we characterize an association between disease progression and DNA methylation in Diffuse Large B cell Lymphoma (DLBCL). By profiling genome-wide DNA methylation at single base-pair resolution in thirteen DLBCL diagnosis-relapse sample pairs, we show DLBCL patients exhibit heterogeneous evolution of tumor methylomes during relapse. We identify differentially methylated regulatory elements and determine a relapse–associated methylation signature converging on key pathways such as transforming growth factor beta (TGF-beta) receptor activity. We also observe decreased intra-tumor methylation heterogeneity from diagnosis to relapsed tumor samples. Relapse-free patients display lower intra-tumor methylation heterogeneity at diagnosis compared to relapsed patients in an independent validation cohort. Furthermore, intra-tumor methylation heterogeneity is predictive of time to relapse. Therefore, we propose that epigenomic heterogeneity may support or drive the relapse phenotype and can be used to predict DLBCL relapse. Using ERRBS, we profiled genome-wide DNA methylation patterns of non-relapse DLBCL tumor samples at diagnosis, relaspe DLBCL patient samples at diagnosis and relaspe.
Project description:Tumor evolution from a single cell into a malignant, heterogeneous tissue remains poorly understood. Here, we profiled single-cell transcriptomes of genetically engineered mouse lung tumors at seven stages, from atypical adenomatous hyperplasia to adenocarcinoma. The diversity of transcriptional states increased over time and was reproducible across tumors and mice. Cancer cells progressively adopted alternate lineage identities, computationally predicted to be mediated through a common transitional, high-plasticity cell state (HPCS). Accordingly, HPCS cells prospectively isolated from mouse tumors and human patient-derived xenografts displayed high capacity for differentiation and proliferation. The HPCS program was associated with poor survival across human cancers and demonstrated chemoresistance in mice. Our study reveals a central principle underpinning intra-tumoral heterogeneity and motivates therapeutic targeting of the HPCS.
Project description:Tumor evolution from a single cell into a malignant, heterogeneous tissue remains poorly understood. Here, we profiled single-cell transcriptomes of genetically engineered mouse lung tumors at seven stages, from atypical adenomatous hyperplasia to adenocarcinoma. The diversity of transcriptional states increased over time and was reproducible across tumors and mice. Cancer cells progressively adopted alternate lineage identities, computationally predicted to be mediated through a common transitional, high-plasticity cell state (HPCS). Accordingly, HPCS cells prospectively isolated from mouse tumors and human patient-derived xenografts displayed high capacity for differentiation and proliferation. The HPCS program was associated with poor survival across human cancers and demonstrated chemoresistance in mice. Our study reveals a central principle underpinning intra-tumoral heterogeneity and motivates therapeutic targeting of the HPCS.
