Mitochondrial DNA (mtDNA) encodes essential components of the respiratory chain and loss of mtDNA leads to mitochondrial dysfunction and neurodegeneration. Mitochondrial transcription factor A (TFAM) is an essential component of mtDNA replication and a regulator of mitochondrial copy number in cells. Studies have shown that TFAM knockdown leads to mitochondrial dysfunction and respiratory chain deficiencies. ATP synthase is Complex V of the mitochondrial respiratory chain. It is driven by a proton gradient between the intermembrane space and the mitochondrial matrix and generates the majority of cellular ATP. The knockdown of coupling factor 6 (Cf6), one of the components of the proton channel F0, causes dysfunction in the complex, leading to mitochondrial dysfunction and respiratory chain deficiencies. Using gene expression analysis, we aimed to investigate the effects of mtDNA dysfunction in the CNS at the molecular level.
Mitochondrial retrograde signaling regulates neuronal function.
Specimen part
View SamplesThe etiology behind cancer-related fatigue (CRF) is currently unknown. The physiological mechanisms of CRF are based on limited evidence that genetic factors, energy expenditure, metabolism, aerobic capacity, and the individual's immune response to inflammation are responsible for the experience of CRF. Gene expression profiling using microarray analysis from white blood cells of men with non-metastatic prostate cancer shows significant, differential expression of 463 probesets during localized external beam radiation therapy (EBRT). Pathway analysis shows a central role of SNCA (alpha-synuclein gene) among these differentially expressed probesets. Significant expression of SNCA was confirmed by qPCR (p<.001) and ELISA (p<.001) over time during EBRT. A significant correlation was noted between averaged fatigue scores and delta CT values of SNCA expression using confirmatory qPCR over time during EBRT (R=-.90, p=.006). Development of fatigue experienced by these men during EBRT may be mediated by SNCA expression. Pathways related to alpha-synuclein may serve as useful biomarkers to understand the mechanisms behind the development of fatigue.
Upregulation of α-synuclein during localized radiation therapy signals the association of cancer-related fatigue with the activation of inflammatory and neuroprotective pathways.
Sex, Specimen part, Disease, Disease stage, Treatment, Subject
View SamplesAn improved understanding of the anti-tumor CD8+ T cell response after checkpoint blockade would enable more informed and effective therapeutic strategies. Here we examined the dynamics of the effector response of CD8+ tumor-infiltrating lymphocytes (TILs) after checkpoint blockade therapy. Bulk and single-cell RNA profiles of CD8+ TILs after combined Tim-3+PD-1 blockade in preclinical models revealed significant changes in the transcriptional profile of PD-1? TILs. These cells could be divided into subsets bearing characterstics of naive-, effector-, and memory-precursor-like cells. Effector- and memory-precursor-like TILs contained tumor-antigen-specific cells, exhibited proliferative and effector capacity, and expanded in response to different checkpoint blockade therapies across different tumor models. The memory-precursor-like subset shared features with CD8+ T cells associated with response to checkpoint blockade in patients and was compromised in the absence of Tcf7. Expression of Tcf7 was requisite for the efficacy of diverse immunotherapies, highlighting the importance of this transcriptional regulator in the development of effective CD8+ T cell responses upon immunotherapy. Overall design: (i) RNAseq of Wild Type Naïve-like, Memory-like and Effector-like subpopulations of PD1-CD8+ Tumor infiltrating lymphocytes isolated from MC38-OVA. CD62LhiSlamf7-CX3CR1-, CD62L-Slamf7hiCX3CR1- and CD62L-Slamf7hiCX3CR1+ subsets within PD-1-CD8+ TILs (ii) RNAseq from WT mice, Tim-3+PD-1+ and Tim-3-PD-1- CD8+ TILs were isolated by cell sorting from MC38-OVA tumor-bearing mice that were treated with anti-PD-1 and anti-Tim-3 antibodies or isotype controls. (iii) Droplet-based single-cell RNA-Seq of Tim-3-PD-1- CD8+ TILs from MC38-OVA tumor-bearing WT mice that were treated with anti-PD-1 and anti-Tim-3 antibodies or isotype controls.
Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1<sup>-</sup>CD8<sup>+</sup> Tumor-Infiltrating T Cells.
Specimen part, Cell line, Treatment, Subject
View SamplesWe report the transcriptional changes in Drosophila after administration of Actin or buffer control Overall design: Examination of transcriptional responses to actin versus buffer injected flies at 3,6 and 24 hours post injection (each time point includes triplicate samples)
Actin is an evolutionarily-conserved damage-associated molecular pattern that signals tissue injury in <i>Drosophila melanogaster</i>.
Sex, Specimen part, Cell line, Subject
View SamplesThe mammalian brain is complex, with multiple cell types performing a variety of diverse functions, but exactly how each cell type is affected in aging remains largely unknown. Here we performed a single-cell transcriptomic analysis of young and old mouse brains. We provide comprehensive datasets of aging-related genes, pathways and ligand–receptor interactions in nearly all brain cell types. Our analysis identified gene signatures that vary in a coordinated manner across cell types and gene sets that are regulated in a cell-type specific manner, even at times in opposite directions. These data reveal that aging, rather than inducing a universal program, drives a distinct transcriptional course in each cell population, and they highlight key molecular processes, including ribosome biogenesis, underlying brain aging. Overall, these large-scale datasets provide a resource for the neuroscience community that will facilitate additional discoveries directed towards understanding and modifying the aging process. Overall design: Total of 16 mice brains with raw data for 50,212 single cells and processed data for 37,089 single cells
Single-cell transcriptomic profiling of the aging mouse brain.
Specimen part, Subject
View SamplesUsing single-cell RNA-seq of intestinal epithelial cells we identify surprising expression of MHC class II, which participates in a novel interaction between gut-resident CD4+ T cells and epithelial stem cells, governing the balance between stem cell differentiation and renewal. Overall design: In the small intestine, a niche of accessory cell types supports the generation of mature epithelial cell types from intestinal stem cells (ISCs). It is unclear, however, if and how immune cells in the niche affect ISC fate or the balance between self-renewal and differentiation. Here, we use single-cell RNA sequencing (scRNA-seq) to identify MHC class II (MHCII) machinery enrichment in two subsets of Lgr5+ ISCs. We show that MHCII+ Lgr5+ ISCs are non-conventional antigen-presenting cells in co-cultures with CD4+ T helper (Th) cells. Stimulation of intestinal organoids with key Th cytokines affects Lgr5+ ISC renewal and differentiation in opposing ways: pro-inflammatory signals promote differentiation, while regulatory cells and cytokines reduce it. In vivo genetic perturbation of Th cells or MHCII expression on Lgr5+ ISCs impacts epithelial cell differentiation and IEC fate during infection. These interactions between Th cells and Lgr5+ ISCs, thus, orchestrate tissue-wide responses to external signals.
T Helper Cell Cytokines Modulate Intestinal Stem Cell Renewal and Differentiation.
Specimen part, Cell line, Treatment, Subject, Time
View SamplesAirways conduct gases to the lung and are disease sites of asthma and cystic fibrosis. Here we study the cellular composition and hierarchy of the mouse tracheal epithelium by single-cell RNA-sequencing (scRNA-seq) and in vivo lineage tracing. We identify a rare cell type, the Foxi1+ pulmonary ionocyte; functional variations in club cells by proximodistal location; a distinct cell type in high turnover squamous epithelial structures that we term ''hillocks''; and disease-relevant subsets of tuft and goblet cells. We developed ''pulse-seq'' , combining scRNA-seq and lineage tracing, to show that tuft, neuroendocrine and ionocyte cells are continually and directly replenished by basal progenitor cells. Ionocytes are the major source of transcripts of the cystic fibrosis transmembrane conductance regulator in both mouse (Cftr) and human (CFTR). Knockout of Foxi1 in mouse ionocytes causes loss of Cftr expression and disrupts airway fluid and mucus physiology, phenotypes that characterize cystic fibrosis. By associating cell-type-specific expression programs with key disease genes, we establish a new cellular narrative for airways disease. Overall design: To understand normal tissue homeostasis, untreated cells were profiled using both 3''-droplet-based and full length plate-based single-cell RNAseq, in combination with genetic reporter-based lineage tracing.
A revised airway epithelial hierarchy includes CFTR-expressing ionocytes.
Specimen part, Cell line, Treatment, Subject, Time
View SamplesTumors from pancreatic cancer specimens obtained at surgery were used for efficacy testing and biologic analysis
Coordinated epidermal growth factor receptor pathway gene overexpression predicts epidermal growth factor receptor inhibitor sensitivity in pancreatic cancer.
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View SamplesGene expression data from 21 triple negative breast cancer samples treated with cisplatin & bevacizumab in the neoadjuvant setting as part of a clinical trial.
Overexpression of BLM promotes DNA damage and increased sensitivity to platinum salts in triple-negative breast and serous ovarian cancers.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression.
Sex, Specimen part
View Samples