Similar Datasets
Project description:Ammonia is a cytotoxic molecule generated during cellular functions and by the gut microbiome. Dysregulated ammonia metabolism initiates a hyperammonemic stress response (HASR). Hyperammonemia occurs in many chronic diseases but there is limited understanding of the overall consequences of HASR. A comprehensive array of unbiased approaches was used to identify global responses during hyperammonemia with experimental validation of critical findings. Protein/gene expression and chromatin accessibility in hyperammonemic murine myotubes and mouse skeletal muscle tissue were analyzed by quantitative proteomics, RNA sequencing (RNAseq), and Assay for Transposase Accessible Chromatin Sequencing (ATACseq). Unique clusters of expression/accessibility changes were identified in hyperammonemic myotubes. In hyperammonemic mouse muscle and myotubes, we identified enrichment of pathways involved in oxidative phosphorylation, calcium signaling, hypoxia inducible factor-1, and apoptosis and regulation of protein synthesis were altered during HASR and were experimentally validated. Enrichment of senescence signaling and glycosylation pathways during HASR were novel observations. Comparisons with RNAseq data from skeletal muscle from human patients with cirrhosis revealed similar perturbations, demonstrating the translational relevance of our observations. We identified several novel regulatory pathways during HASR that are conserved in different models and across species, and whose dysregulation could significantly impact skeletal muscle structure and function.
2021-07-27 | PXD025321 | Pride
Project description:Ammonia is a cytotoxic molecule generated during cellular functions and by the gut microbiome. Dysregulated ammonia metabolism initiates a hyperammonemic stress response (HASR). Hyperammonemia occurs in many chronic diseases but there is limited understanding of the overall consequences of HASR. A comprehensive array of unbiased approaches was used to identify global responses during hyperammonemia with experimental validation of critical findings. Protein/gene expression and chromatin accessibility in hyperammonemic murine myotubes and mouse skeletal muscle tissue were analyzed by quantitative proteomics, RNA sequencing (RNAseq), and Assay for Transposase Accessible Chromatin Sequencing (ATACseq). Unique clusters of expression/accessibility changes were identified in hyperammonemic myotubes. In hyperammonemic mouse muscle and myotubes, we identified enrichment of pathways involved in oxidative phosphorylation, calcium signaling, hypoxia inducible factor-1, and apoptosis and regulation of protein synthesis were altered during HASR and were experimentally validated. Enrichment of senescence signaling and glycosylation pathways during HASR were novel observations. Comparisons with RNAseq data from skeletal muscle from human patients with cirrhosis revealed similar perturbations, demonstrating the translational relevance of our observations. We identified several novel regulatory pathways during HASR that are conserved in different models and across species, and whose dysregulation could significantly impact skeletal muscle structure and function.
2021-07-28 | GSE171642 | GEO
Project description:Ammonia is a cytotoxic molecule generated during cellular functions and by the gut microbiome. Dysregulated ammonia metabolism initiates a hyperammonemic stress response (HASR). Hyperammonemia occurs in many chronic diseases but there is limited understanding of the overall consequences of HASR. A comprehensive array of unbiased approaches was used to identify global responses during hyperammonemia with experimental validation of critical findings. Protein/gene expression and chromatin accessibility in hyperammonemic murine myotubes and mouse skeletal muscle tissue were analyzed by quantitative proteomics, RNA sequencing (RNAseq), and Assay for Transposase Accessible Chromatin Sequencing (ATACseq). Unique clusters of expression/accessibility changes were identified in hyperammonemic myotubes. In hyperammonemic mouse muscle and myotubes, we identified enrichment of pathways involved in oxidative phosphorylation, calcium signaling, hypoxia inducible factor-1, and apoptosis and regulation of protein synthesis were altered during HASR and were experimentally validated. Enrichment of senescence signaling and glycosylation pathways during HASR were novel observations. Comparisons with RNAseq data from skeletal muscle from human patients with cirrhosis revealed similar perturbations, demonstrating the translational relevance of our observations. We identified several novel regulatory pathways during HASR that are conserved in different models and across species, and whose dysregulation could significantly impact skeletal muscle structure and function.
2021-07-28 | GSE171644 | GEO
Project description:Ammonia is a cytotoxic molecule generated during cellular functions and by the gut microbiome. Dysregulated ammonia metabolism initiates a hyperammonemic stress response (HASR). Hyperammonemia occurs in many chronic diseases but there is limited understanding of the overall consequences of HASR. A comprehensive array of unbiased approaches was used to identify global responses during hyperammonemia with experimental validation of critical findings. Protein/gene expression and chromatin accessibility in hyperammonemic murine myotubes and mouse skeletal muscle tissue were analyzed by quantitative proteomics, RNA sequencing (RNAseq), and Assay for Transposase Accessible Chromatin Sequencing (ATACseq). Unique clusters of expression/accessibility changes were identified in hyperammonemic myotubes. In hyperammonemic mouse muscle and myotubes, we identified enrichment of pathways involved in oxidative phosphorylation, calcium signaling, hypoxia inducible factor-1, and apoptosis and regulation of protein synthesis were altered during HASR and were experimentally validated. Enrichment of senescence signaling and glycosylation pathways during HASR were novel observations. Comparisons with RNAseq data from skeletal muscle from human patients with cirrhosis revealed similar perturbations, demonstrating the translational relevance of our observations. We identified several novel regulatory pathways during HASR that are conserved in different models and across species, and whose dysregulation could significantly impact skeletal muscle structure and function.
2021-07-28 | GSE171643 | GEO
Project description:Integrated molecular landscape perturbations underlie cellular responses during hyperammonemia
| PRJNA720399 | ENA
Project description:Integrated molecular landscape perturbations underlie cellular responses during hyperammonemia [ATAC-seq]
| PRJNA720401 | ENA
Project description:Integrated molecular landscape perturbations underlie cellular responses during hyperammonemia [mouse RNA-seq]
| PRJNA720403 | ENA
Project description:Integrated molecular landscape perturbations underlie cellular responses during hyperammonemia [human RNA-seq]
| PRJNA720402 | ENA
Project description:Ammonia is a cytotoxic molecule generated during normal cellular functions. Dysregulated ammonia metabolism, which is evident in many chronic diseases such as liver cirrhosis, heart failure, and chronic obstructive pulmonary disease, initiates a hyperammonemic stress response in tissues including skeletal muscle and in myotubes. Perturbations in levels of specific regulatory molecules have been reported, but the global responses to hyperammonemia are unclear. In this study, we used a multiomics approach to vertically integrate unbiased data generated using an assay for transposase-accessible chromatin with high-throughput sequencing, RNA-Seq, and proteomics. We then horizontally integrated these data across different models of hyperammonemia, including myotubes and mouse and human muscle tissues. Changes in chromatin accessibility and/or expression of genes resulted in distinct clusters of temporal molecular changes including transient, persistent, and delayed responses during hyperammonemia in myotubes. Known responses to hyperammonemia, including mitochondrial and oxidative dysfunction, protein homeostasis disruption, and oxidative stress pathway activation, were enriched in our datasets. During hyperammonemia, pathways that impact skeletal muscle structure and function that were consistently enriched were those that contribute to mitochondrial dysfunction, oxidative stress, and senescence. We made several novel observations, including an enrichment in antiapoptotic B-cell leukemia/lymphoma 2 family protein expression, increased calcium flux, and increased protein glycosylation in myotubes and muscle tissue upon hyperammonemia. Critical molecules in these pathways were validated experimentally. Human skeletal muscle from patients with cirrhosis displayed similar responses, establishing translational relevance. These data demonstrate complex molecular interactions during adaptive and maladaptive responses during the cellular stress response to hyperammonemia.
| S-EPMC8424232 | biostudies-literature
Project description:Cellular populations have been widely observed to respond heterogeneously to perturbation. However, interpreting the observed heterogeneity is an extremely challenging problem because of the complexity of possible cellular phenotypes, the large dimension of potential perturbations, and the lack of methods for separating meaningful biological information from noise. Here, we develop an image-based approach to characterize cellular phenotypes based on patterns of signaling marker colocalization. Heterogeneous cellular populations are characterized as mixtures of phenotypically distinct subpopulations, and responses to perturbations are summarized succinctly as probabilistic redistributions of these mixtures. We apply our method to characterize the heterogeneous responses of cancer cells to a panel of drugs. We find that cells treated with drugs of (dis-)similar mechanism exhibit (dis-)similar patterns of heterogeneity. Despite the observed phenotypic diversity of cells observed within our data, low-complexity models of heterogeneity were sufficient to distinguish most classes of drug mechanism. Our approach offers a computational framework for assessing the complexity of cellular heterogeneity, investigating the degree to which perturbations induce redistributions of a limited, but nontrivial, repertoire of underlying states and revealing functional significance contained within distinct patterns of heterogeneous responses.
| S-EPMC2614757 | biostudies-literature