Small molecule inhibitors of the bromodomain and extraterminal (BET) family of proteins are in clinical trials for a variety of cancers, but patient selection strategies are limited. This is due in part to the heterogeneity of response following BET inhibition (BETi), which includes differentiation, senescence, and cell death in subsets of cancer cell lines. To elucidate the dominant features defining response to BETi, we carried out phenotypic and gene expression analysis of both treatment naÃ¯ve cell lines and engineered tolerant lines. We found that both de novo and acquired tolerance to BET inhibition are driven by the robustness of the apoptotic response and that genetic or pharmacological manipulation of the apoptotic signaling network can modify the phenotypic response to BETi. We further identify that ordered expression of the apoptotic genes BCL2, BCL2L1, and BAD significantly predicts response to BETi. Our findings highlight the role of the apoptotic network in response to BETi, providing a molecular basis for patient stratification and combination therapies. Overall design: Gene expression profiling of A375 melanoma cells or NOMO-1 AML cells treated with DMSO or the BET inhibitor, CPI203. Also, gene expression profiling of the respective derived BETi-tolerant cells treated with DMSO or CPI203.
Preclinical Anticancer Efficacy of BET Bromodomain Inhibitors Is Determined by the Apoptotic Response.
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The transition to lactation challenges dairy cows metabolically. Immune dysfunction and infectious disease risk is the hallmark of this transition period. Transcriptome data of PBMC shows differentially expressed pathways postpartum. Metabolically stressed cows show upregulation of innate immune pathways and inflammation. Overall design: Gene expression profiling of PMBCs from 6 dairy cows, each sampled 21 days prepartum and 7 days postpartum. Three cows (H1-3) showed signs of increased metabolic stress (by other assays) relative to the other three cows (L1-3).
The degree of postpartum metabolic challenge in dairy cows is associated with peripheral blood mononuclear cell transcriptome changes of the innate immune system.
Specimen part, SubjectView Samples
Identification of temporal changes in gene expression in macrophages isolated from the site of nerve injury. Overall design: Macrophages were profiled at 3 timepoints (5, 14, and 28 days) after nerve injury with 2-3 independent biological replicates per timepoint.
Temporal changes in macrophage phenotype after peripheral nerve injury.
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This analysis represents the first comprehensive sampling of germ cells in the developing testis over time, at high-resolution, single-cell depth. From these analyses, we have not only revealed novel genetic regulatory signatures of murine germ cells over time, but have also demonstrated that cell types positive for a single marker gene have the capacity to change dramatically during testis maturation, and therefore cells of a particular “identity” may differ significantly from postnatal to adult life. Overall design: Single-cell suspensions of mammalian testes ranging from PND6 to adult were processed for single-cell RNAseq (10x Genomics Chromium) and libraries were sequenced on a NextSeq500 (Illumina).
Dynamic transcriptome profiles within spermatogonial and spermatocyte populations during postnatal testis maturation revealed by single-cell sequencing.
Age, Disease, Cell line, SubjectView Samples
Our laboratory wanted to define the transcription profile of aged skeletal muscle. For this reason, we performed a triplicate microarray study on young (3 weeks) and aged (24 months) gatrocnemius muscle from wild-type C57B16 Mice
Transcriptional profiling of skeletal muscle reveals factors that are necessary to maintain satellite cell integrity during ageing.
BPH/5 mice are an inbred strain with “borderline hypertension” that spontaneously develops both maternal and fetal hallmarks of preeclampsia. RNA-Seq analysis of BPH/5 uterine implantation sites at embryonic day 7.5, the peak of decidualization, identifies differential expression of inflammatory response genes, including members of the complement family, compared to C57 controls. Overall design: RNA-Seq was performed on RNA isolated from E7.5 BPH/5 and C57 implantation sites (n=4).
Angiogenic factor imbalance precedes complement deposition in placentae of the BPH/5 model of preeclampsia.
Cell line, SubjectView Samples
Sickle cell disease (SCD) is caused by a pathogenic hemoglobin (Hb) mutation, yet patients can have dramatically variable clinical manifestations. Here we address the genetic basis of this clinical heterogeneity. Using a systems genetics approach, we performed whole blood gene expression analysis and eQTL analysis on different clinical phenotypes in SCD patients.
Genomic architecture of sickle cell disease in West African children.
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Access to an unlimited number of human pancreatic beta cells represents a major challenge in the field of diabetes to better dissect human beta cell functions and to make significant progress in drug discovery and cell replacement therapies. We previously reported the generation of the EndoC-bH1 human beta cell line that was generated by targeted oncogenesis in human fetal pancreases followed by in vivo cell differentiation in mice. Such cell line displayed many functional properties of adult beta cells. Here we devised a novel strategy to generate conditionally immortalized human beta cell lines based on CRE-mediated excision of immortalizing transgenes. The resulting EndoC-bH2 cell line can be massively amplified in vitro. Transgenes are next efficiently excised upon CRE expression leading to cell proliferation arrest and strong enhancement of beta cell specific features such as insulin expression, content and secretion. Excised EndoC-bH2 cells are close to authentic human beta cells and represent a unique tool to further study beta cell function and to understand why adult human beta cells are refractory to proliferation and how to achieve drug-dependent mobilization towards beta cell expansion.
Development of a conditionally immortalized human pancreatic β cell line.
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During immune ontogeny the thymus is colonized by distinct waves of hematopoietic stem cells that give rise to unique lineages of immune cells. In this report, we asked whether the developmental origin of CD8+ T cells influences their response to infection later in adulthood. To answer this question, we developed a system to 'timestamp' CD8+ T cells in situ at various stages of development (1d and 28d) and examined their behavior at 8 weeks of age. We found that neonatal-derived CD8+ T cells have an intrinsic propensity to become memory phenotype cells prior to infection and are the first cells to proliferate and become effectors after microbial challenge. These data indicate that there are developmental layers in the adult CD8+ T cell response to infection and that the heterogeneity in the effector pool is linked to the variation in the developmental origins of the responding cells. This dataset profiles gene expression in 1day- and 28day-timestamped naïve CD8+ T cells in 8 week old mice. Overall design: gene expression profiling of naïve CD8+ T cells in 8 week old mice, looking at two samples: cells made at 1 day or 28 days of life, in duplicate.
Developmental Origin Governs CD8<sup>+</sup> T Cell Fate Decisions during Infection.
Specimen part, SubjectView Samples
Soybean (Glycine max) seeds are an important source of seed storage compounds, including protein, oil, and sugar used for food, feed, chemical, and biofuel production. We assessed detailed temporal transcriptional and metabolic changes in developing soybean embryos to gain a systems biology view of developmental and metabolic changes and to identify potential targets for metabolic engineering. Two major developmental and metabolic transitions were captured enabling identification of potential metabolic engineering targets specific to seed filling and to desiccation. The first transition involved a switch between different types of metabolism in dividing and elongating cells. The second transition involved the onset of maturation and desiccation tolerance during seed filling and a switch from photoheterotrophic to heterotrophic metabolism. Clustering analyses of metabolite and transcript data revealed clusters of functionally related metabolites and transcripts active in these different developmental and metabolic programs. The gene clusters provide a resource to generate predictions about the associations and interactions of unknown regulators with their targets based on guilt-by-association relationships. The inferred regulators also represent potential targets for future metabolic engineering of relevant pathways and steps in central carbon and nitrogen metabolism in soybean embryos and drought and desiccation tolerance in plants. Overall design: Total mRNA profiles of 10 time course samples of Soybean developing embryos with three replicates per sample were generated by deep sequencing, using Illumina HiSeq 2000
Transcriptome-wide functional characterization reveals novel relationships among differentially expressed transcripts in developing soybean embryos.
Age, Specimen part, Cell line, SubjectView Samples