Effector cells for adoptive immunotherapy can be generated by in vitro stimulation of nave or memory subsets of CD8+ T cells. While the characteristics of CD8+ T cell subsets are well defined, the heritable influence of those populations on their effector cell progeny is not well understood. We studied effector cells generated from nave or central memory CD8+ T cells and found that they retained distinct gene expression signatures and developmental programs. Effector cells derived from central memory cells tended to retain their CD62L+ phenotype, but also to acquire KLRG1, an indicator of cellular senescence. In contrast, the effector cell progeny of nave cells displayed reduced terminal differentiation, and, following infusion, they displayed greater expansion, cytokine production, and tumor destruction. These data indicate that effector cells retain a gene expression imprint conferred by their nave or central memory progenitors, and they suggest a strategy for enhancing cancer immunotherapy.
Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity.
Specimen part
View SamplesNon-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in industrialized countries. Liver samples from morbidly obese patients (N=45) with all stages of NAFLD and controls (N=18) were analysed by array-based DNA methylation and mRNA expression profiling. NAFLD-specific expression and methylation differences were seen for nine genes coding for key enzymes in intermediate metabolism (including PC, ACLY, PLCG1) and insulin/insulin-like signalling (including IGF1, IGFBP2, PRKCE) and replicated by bisulfite pyrosequening (independent N=39). Transcription factor binding sites at NAFLD-specific CpG sites were >1000-fold enriched for ZNF274, PGC1A and SREBP2. Intra-individual comparison of liver biopsies before and after bariatric surgery showed NAFLD-associated methylation changes to be partially reversible. Post-bariatric and NAFLD-specific methylation signatures were clearly distinct both in gene-ontology and transcription factor binding site analyses, with >400-fold enrichment of NRF1, HSF1 and ESRRA sites. Our findings provide one of the first examples of treatment-induced epigenetic organ remodelling in humans.
DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery.
Sex, Age, Specimen part
View SamplesAlveolar rhabdomyosarcoma (aRMS) is a soft tissue sarcoma associated with the skeletal muscle lineage. The majority of aRMS tumors express the fusion protein PAX3-FOXO1 (PF), which has proven chemically intractable. As such, we identified proteins downstream from or cooperate with PF to support tumorigenesis, including SFRP3 (FRZB). Suppression of SFRP3 using lentivirally transduced shRNAs inhibits cell growth in vitro and tumor growth in vivo. This study aims to identify the genetic changes that underlie the SFRP3 suppression-mediated decreased cell growth. We analyzed changes using Gene Ontology (GO) enrichment and found the induced genes were enriched in striated muscle development/differentiation. In contrast, the repressed genes were enriched in response to stimulus and cell cycle/mitosis genes. We also observed as expected downregulation of SFRP3 (FRZB) but also downregulation of Wnt pathway-repressing genes such as CTBP2 (a transcriptional repressor of TCF, similar to CTBP1 ) and NAV2 (which is downstream from APC). Conversely, we noted upregulation of genes including CCND1 (cyclin D1) and SNAI2 (SLUG), both Wnt signaling target genes and WNT6, which is known to inhibit myoblast proliferation but induce myoblast elongation.
Secreted Frizzled-Related Protein 3 (SFRP3) Is Required for Tumorigenesis of PAX3-FOXO1-Positive Alveolar Rhabdomyosarcoma.
Disease, Cell line, Treatment
View SamplesTo investigate transcriptional differences between HCM and WT cells Overall design: Examination of HCM vs WT Cells, with 3 replicates of each sample
A Contraction Stress Model of Hypertrophic Cardiomyopathy due to Sarcomere Mutations.
Specimen part, Disease, Disease stage, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer.
Specimen part, Treatment
View SamplesAnalysis of differentiating LSD1-KD C2C12 myoblasts. We found LSD1 is an important regulator of oxidative phenotypes in skeletal muscle cells.
LSD1 mediates metabolic reprogramming by glucocorticoids during myogenic differentiation.
Specimen part, Cell line
View SamplesAnalysis of differentiating C2C12 myoblasts treated with two LSD1 specific inhibitors. We found LSD1 is an important regulator of oxidative phenotypes in skeletal muscle cells. Results provide insight into the molecular mechanisms underlying roles of LSD1 in myocytes.
LSD1 mediates metabolic reprogramming by glucocorticoids during myogenic differentiation.
Specimen part, Cell line
View SamplesDuring cold acclimation plants increase their freezing tolerance in response to low non-freezing temperatures. This is accompanied by many physiological, biochemical and molecular changes that have been extensively investigated. In addition, many cold acclimated plants become more freezing tolerant during exposure to mild, non-damaging sub-zero temperatures. There is hardly any information available about the molecular basis of this adaptation. However, Arabidopsis thaliana is among the species that acclimate to sub-zero temperatures. This makes it possible to use the molecular and genetic tools available in this species to identify components of sub-zero signal transduction and acclimation. Here, we have used microarrays and a qRT-PCR primer platform covering 1880 genes encoding transcription factors to monitor changes in gene expression in the accessions Columbia-0, Rschew and Tenela during the first three days of sub-zero acclimation at -3C. The results indicate that gene expression during sub-zero acclimation follows a tighly controlled time-course. Especially AP2/EREBP and WRKY transcription factors may be important regulators of sub-zero acclimation, although the CBF signal transduction pathway seems to be less important during sub-zero than during cold acclimation. Globally, we estimate that approximately 5% of all Arabidopsis genes are regulated during sub-zero acclimation. Particularly photosynthesis-related genes were down-regulated and genes belonging to the functional classes of cell wall biosynthesis, hormone metabolism and RNA regulation of transcription were up-regulated. Collectively, these data provide the first global analysis of gene expression during sub-zero acclimation and allow the identification of candidate genes for forward and reverse genetic studies into the molecular mechanisms of sub-zero acclimation.
Global changes in gene expression, assayed by microarray hybridization and quantitative RT-PCR, during acclimation of three Arabidopsis thaliana accessions to sub-zero temperatures after cold acclimation.
Specimen part, Time
View SamplesHow neurons are wired to form precise circuits is crucial to understand the development of cortical functions. Glutamatergic pyramidal cell and GABAergic interneuron wire up the cortex through differentiated cellular events. However, little is known about the molecular mechanisms that underlie the unique features of interneuron wiring.
The Microtubule Regulator NEK7 Coordinates the Wiring of Cortical Parvalbumin Interneurons.
Specimen part
View SamplesEndometrial receptivity on genomic level is one of the major cause of implantation failure in IVF patients with unexlained infertility and is a main obstacle in success of IVF. Gene expression profiles of implantation failure cases of unexplained infertility were compared with proven healthy oocyte donors as controls, both undergoing ovarian stimulation. The results provide additional information about gene expression profile related to endometrial receptivity in implantation failure cases especially under the influence of ovarian stimulation during IVF cycle.
Downregulation of genes related to immune and inflammatory response in IVF implantation failure cases under controlled ovarian stimulation.
Age, Specimen part
View Samples