The Integrated "Multiomics" Landscape at Peak Injury and Resolution From Alcohol-Associated Liver Disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA845940 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19581955.fastq.gz | Fastqsanger.gz | |||
| SRR19581956.fastq.gz | Fastqsanger.gz | |||
| SRR19581957.fastq.gz | Fastqsanger.gz | |||
| SRR19581958.fastq.gz | Fastqsanger.gz | |||
| SRR19581959.fastq.gz | Fastqsanger.gz |
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Project description:To investigate the the liver transcriptome at peak injury and during early and late resolution from alcohol-induced liver injury in mice
2022-06-06 | GSE205484 | GEO
Project description:Background. Skeletal muscle is a major target organ for ethanol induced perturbations with resultant sarcopenia in alcohol-related liver disease (ALD). Targeted studies show that in skeletal muscle, ethanol causes mitochondrial oxidative dysfunction and impaired mTORC1 signaling with consequent decreased protein synthesis and increased autophagy. However, complex interactions and pathway intersections involved in cellular adaptive and maladaptive responses are not well understood. Unlike hypotheses driven focused experiments, an integrated multiomics-experimental validation approach helps identify the global landscape of complex, interacting perturbations in the skeletal muscle. Methods. We used an integrated multiomics approach in a comprehensive array of models, including murine and human induced pluripotent stem cell-derived myotubes (hiPSCm), skeletal muscle from a mouse model of ALD (mALD), and human patients with alcohol-related cirrhosis (CIR) and controls (CON), to identify novel regulatory mechanisms of sarcopenia in ALD. We generated 13 untargeted datasets, including chromosomal conformation, RNA sequencing, proteomics, phosphoproteomics, acetylomics, and metabolomics and conducted a comprehensive analysis using upset plots and feature extraction-based approaches. The most altered molecular interactions were experimentally validated in different models using immunoblots, redox measurements, imaging methods, and measures of senescence associated molecular phenotype (SAMP). Redox ratio was reversed using mitochondrial targeted Lactobacillus brevis NADH oxidase (MitoLbNOX). Results. Enrichments in mitochondrial oxidative function, protein synthesis, and senescence pathways were identified. Multiomics analyses were consistent with the known effects of hypoxia inducible factor 1 (HIF1) that inhibits mitochondrial oxidative dysfunction and promotes skeletal muscle senescence. Pertubrations in genes in the nicotinamide dinucleotide-related pathways including sirtuin signaling, known regulators of senescence, was also noted with ethanol treatment. Experimentally, HIF1 protein was stabilized in myotubes and muscle tissue without cellular hypoxia. Mitochondrial electron transport chain protein expression was less in murine myotubes and hiPSCm with lower redox ratio, less expression of sirtuins, and increased acetylation of mitochondrial proteins. SAMP noted in multiple models in response to ethanol exposure and reversing redox ratio with MitoLbNOX prevented HIF1a stabilization and SAMP in murine myotubes. Conclusions. Our integrated multiomics analyses combined with complementary experimental validation, identify HIF1a stabilization with accelerated skeletal muscle post-mitotic senescence as novel mechanisms of sarcopenia in ALD, highlighting the complex interactions that result in mitochondrial dysfunction with persistent and progressive sarcopenia in ALD.
2025-06-13 | PXD057550 | Pride
Project description:Background. Skeletal muscle is a major target organ for ethanol induced perturbations with resultant sarcopenia in alcohol-related liver disease (ALD). Targeted studies show that in skeletal muscle, ethanol causes mitochondrial oxidative dysfunction and impaired mTORC1 signaling with consequent decreased protein synthesis and increased autophagy. However, complex interactions and pathway intersections involved in cellular adaptive and maladaptive responses are not well understood. Unlike hypotheses driven focused experiments, an integrated multiomics-experimental validation approach helps identify the global landscape of complex, interacting perturbations in the skeletal muscle. Methods. We used an integrated multiomics approach in a comprehensive array of models, including murine and human induced pluripotent stem cell-derived myotubes (hiPSCm), skeletal muscle from a mouse model of ALD (mALD), and human patients with alcohol-related cirrhosis (CIR) and controls (CON), to identify novel regulatory mechanisms of sarcopenia in ALD. We generated 13 untargeted datasets, including chromosomal conformation, RNA sequencing, proteomics, phosphoproteomics, acetylomics, and metabolomics and conducted a comprehensive analysis using upset plots and feature extraction-based approaches. The most altered molecular interactions were experimentally validated in different models using immunoblots, redox measurements, imaging methods, and measures of senescence associated molecular phenotype (SAMP). Redox ratio was reversed using mitochondrial targeted Lactobacillus brevis NADH oxidase (MitoLbNOX). Results. Enrichments in mitochondrial oxidative function, protein synthesis, and senescence pathways were identified. Multiomics analyses were consistent with the known effects of hypoxia inducible factor 1 (HIF1) that inhibits mitochondrial oxidative dysfunction and promotes skeletal muscle senescence. Pertubrations in genes in the nicotinamide dinucleotide-related pathways including sirtuin signaling, known regulators of senescence, was also noted with ethanol treatment. Experimentally, HIF1 protein was stabilized in myotubes and muscle tissue without cellular hypoxia. Mitochondrial electron transport chain protein expression was less in murine myotubes and hiPSCm with lower redox ratio, less expression of sirtuins, and increased acetylation of mitochondrial proteins. SAMP noted in multiple models in response to ethanol exposure and reversing redox ratio with MitoLbNOX prevented HIF1a stabilization and SAMP in murine myotubes. Conclusions. Our integrated multiomics analyses combined with complementary experimental validation, identify HIF1a stabilization with accelerated skeletal muscle post-mitotic senescence as novel mechanisms of sarcopenia in ALD, highlighting the complex interactions that result in mitochondrial dysfunction with persistent and progressive sarcopenia in ALD.
2025-06-25 | PXD057409 | Pride
Project description:Background. Skeletal muscle is a major target organ for ethanol induced perturbations with resultant sarcopenia in alcohol-related liver disease (ALD). Targeted studies show that in skeletal muscle, ethanol causes mitochondrial oxidative dysfunction and impaired mTORC1 signaling with consequent decreased protein synthesis and increased autophagy. However, complex interactions and pathway intersections involved in cellular adaptive and maladaptive responses are not well understood. Unlike hypotheses driven focused experiments, an integrated multiomics-experimental validation approach helps identify the global landscape of complex, interacting perturbations in the skeletal muscle. Methods. We used an integrated multiomics approach in a comprehensive array of models, including murine and human induced pluripotent stem cell-derived myotubes (hiPSCm), skeletal muscle from a mouse model of ALD (mALD), and human patients with alcohol-related cirrhosis (CIR) and controls (CON), to identify novel regulatory mechanisms of sarcopenia in ALD. We generated 13 untargeted datasets, including chromosomal conformation, RNA sequencing, proteomics, phosphoproteomics, acetylomics, and metabolomics and conducted a comprehensive analysis using upset plots and feature extraction-based approaches. The most altered molecular interactions were experimentally validated in different models using immunoblots, redox measurements, imaging methods, and measures of senescence associated molecular phenotype (SAMP). Redox ratio was reversed using mitochondrial targeted Lactobacillus brevis NADH oxidase (MitoLbNOX). Results. Enrichments in mitochondrial oxidative function, protein synthesis, and senescence pathways were identified. Multiomics analyses were consistent with the known effects of hypoxia inducible factor 1 (HIF1) that inhibits mitochondrial oxidative dysfunction and promotes skeletal muscle senescence. Pertubrations in genes in the nicotinamide dinucleotide-related pathways including sirtuin signaling, known regulators of senescence, was also noted with ethanol treatment. Experimentally, HIF1 protein was stabilized in myotubes and muscle tissue without cellular hypoxia. Mitochondrial electron transport chain protein expression was less in murine myotubes and hiPSCm with lower redox ratio, less expression of sirtuins, and increased acetylation of mitochondrial proteins. SAMP noted in multiple models in response to ethanol exposure and reversing redox ratio with MitoLbNOX prevented HIF1a stabilization and SAMP in murine myotubes. Conclusions. Our integrated multiomics analyses combined with complementary experimental validation, identify HIF1a stabilization with accelerated skeletal muscle post-mitotic senescence as novel mechanisms of sarcopenia in ALD, highlighting the complex interactions that result in mitochondrial dysfunction with persistent and progressive sarcopenia in ALD.
2025-06-13 | PXD057544 | Pride
Project description:Background. Skeletal muscle is a major target organ for ethanol induced perturbations with resultant sarcopenia in alcohol-related liver disease (ALD). Targeted studies show that in skeletal muscle, ethanol causes mitochondrial oxidative dysfunction and impaired mTORC1 signaling with consequent decreased protein synthesis and increased autophagy. However, complex interactions and pathway intersections involved in cellular adaptive and maladaptive responses are not well understood. Unlike hypotheses driven focused experiments, an integrated multiomics-experimental validation approach helps identify the global landscape of complex, interacting perturbations in the skeletal muscle. Methods. We used an integrated multiomics approach in a comprehensive array of models, including murine and human induced pluripotent stem cell-derived myotubes (hiPSCm), skeletal muscle from a mouse model of ALD (mALD), and human patients with alcohol-related cirrhosis (CIR) and controls (CON), to identify novel regulatory mechanisms of sarcopenia in ALD. We generated 13 untargeted datasets, including chromosomal conformation, RNA sequencing, proteomics, phosphoproteomics, acetylomics, and metabolomics and conducted a comprehensive analysis using upset plots and feature extraction-based approaches. The most altered molecular interactions were experimentally validated in different models using immunoblots, redox measurements, imaging methods, and measures of senescence associated molecular phenotype (SAMP). Redox ratio was reversed using mitochondrial targeted Lactobacillus brevis NADH oxidase (MitoLbNOX). Results. Enrichments in mitochondrial oxidative function, protein synthesis, and senescence pathways were identified. Multiomics analyses were consistent with the known effects of hypoxia inducible factor 1 (HIF1) that inhibits mitochondrial oxidative dysfunction and promotes skeletal muscle senescence. Pertubrations in genes in the nicotinamide dinucleotide-related pathways including sirtuin signaling, known regulators of senescence, was also noted with ethanol treatment. Experimentally, HIF1 protein was stabilized in myotubes and muscle tissue without cellular hypoxia. Mitochondrial electron transport chain protein expression was less in murine myotubes and hiPSCm with lower redox ratio, less expression of sirtuins, and increased acetylation of mitochondrial proteins. SAMP noted in multiple models in response to ethanol exposure and reversing redox ratio with MitoLbNOX prevented HIF1a stabilization and SAMP in murine myotubes. Conclusions. Our integrated multiomics analyses combined with complementary experimental validation, identify HIF1a stabilization with accelerated skeletal muscle post-mitotic senescence as novel mechanisms of sarcopenia in ALD, highlighting the complex interactions that result in mitochondrial dysfunction with persistent and progressive sarcopenia in ALD.
2025-06-13 | PXD057502 | Pride
Project description:Alcohol-associated liver disease (ALD) is a significant clinical problem for which the most effective therapy is alcohol abstinence. The two aims of this study were, first, to identify the liver transcriptome, fecal microbiome, and portal serum metabolome at peak injury and during early and late resolution from ALD; and second, to integrate their interactions and understand better the pathogenesis of ALD. To provoke alcohol-induced liver injury, female and male wild-type mice were fed the control or ethanol Lieber-DeCarli diets for 6 weeks. To study early and late resolution, alcohol was withdrawn from the diet and mice were sacrificed after 3 and 14 days, respectively. At peak injury, there was increased signal transducer and activator of transcription (Stat3), Rho-GTPases, Tec kinase and glycoprotein VI (Gp6), and decreased peroxisome proliferator-activated receptor signaling. During resolution from ALD, there was up-regulation of vitamin D receptor/retinoid X receptor, toll-like receptor, p38 and Stat3, and down-regulation of liver X receptor signaling. Females showed significant changes in catabolic pathways, whereas males increased cellular stress, injury, and immune-response pathways that decreased during resolution. The bacterial genus Alistipes and the metabolite dipeptide glycyl-L-leucine increased at peak but decreased during resolution from ALD in both genders. Hepatic induction of mitogen-activated protein kinase (Map3k1) correlated with changes in the microbiome and metabolome at peak but was restored during ALD resolution. Inhibition of MAP3K1 protected from ALD in mice. Conclusion: Alcohol abstinence restores the liver transcriptome, fecal microbiome, and portal serum metabolome in a gender-specific manner. Integration of multiomics data identified Map3k1 as a key gene driving pathogenesis and resolution from ALD.
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Project description:Background. Skeletal muscle is a major target organ for ethanol induced perturbations with resultant sarcopenia in alcohol-related liver disease (ALD). Targeted studies show that in skeletal muscle, ethanol causes mitochondrial oxidative dysfunction and impaired mTORC1 signaling with consequent decreased protein synthesis and increased autophagy. However, complex interactions and pathway intersections involved in cellular adaptive and maladaptive responses are not well understood. Unlike hypotheses driven focused experiments, an integrated multiomics-experimental validation approach helps identify the global landscape of complex, interacting perturbations in the skeletal muscle. Methods. We used an integrated multiomics approach in a comprehensive array of models, including murine and human induced pluripotent stem cell-derived myotubes (hiPSCm), skeletal muscle from a mouse model of ALD (mALD), and human patients with alcohol-related cirrhosis (CIR) and controls (CON), to identify novel regulatory mechanisms of sarcopenia in ALD. We generated 13 untargeted datasets, including chromosomal conformation, RNA sequencing, proteomics, phosphoproteomics, acetylomics, and metabolomics and conducted a comprehensive analysis using upset plots and feature extraction-based approaches. The most altered molecular interactions were experimentally validated in different models using immunoblots, redox measurements, imaging methods, and measures of senescence associated molecular phenotype (SAMP). Redox ratio was reversed using mitochondrial targeted Lactobacillus brevis NADH oxidase (MitoLbNOX). Results. Enrichments in mitochondrial oxidative function, protein synthesis, and senescence pathways were identified. Multiomics analyses were consistent with the known effects of hypoxia inducible factor 1 (HIF1) that inhibits mitochondrial oxidative dysfunction and promotes skeletal muscle senescence. Pertubrations in genes in the nicotinamide dinucleotide-related pathways including sirtuin signaling, known regulators of senescence, was also noted with ethanol treatment. Experimentally, HIF1 protein was stabilized in myotubes and muscle tissue without cellular hypoxia. Mitochondrial electron transport chain protein expression was less in murine myotubes and hiPSCm with lower redox ratio, less expression of sirtuins, and increased acetylation of mitochondrial proteins. SAMP noted in multiple models in response to ethanol exposure and reversing redox ratio with MitoLbNOX prevented HIF1a stabilization and SAMP in murine myotubes. Conclusions. Our integrated multiomics analyses combined with complementary experimental validation, identify HIF1a stabilization with accelerated skeletal muscle post-mitotic senescence as novel mechanisms of sarcopenia in ALD, highlighting the complex interactions that result in mitochondrial dysfunction with persistent and progressive sarcopenia in ALD.
2025-06-13 | PXD057554 | Pride
Project description:Background. Skeletal muscle is a major target organ for ethanol induced perturbations with resultant sarcopenia in alcohol-related liver disease (ALD). Targeted studies show that in skeletal muscle, ethanol causes mitochondrial oxidative dysfunction and impaired mTORC1 signaling with consequent decreased protein synthesis and increased autophagy. However, complex interactions and pathway intersections involved in cellular adaptive and maladaptive responses are not well understood. Unlike hypotheses driven focused experiments, an integrated multiomics-experimental validation approach helps identify the global landscape of complex, interacting perturbations in the skeletal muscle. Methods. We used an integrated multiomics approach in a comprehensive array of models, including murine and human induced pluripotent stem cell-derived myotubes (hiPSCm), skeletal muscle from a mouse model of ALD (mALD), and human patients with alcohol-related cirrhosis (CIR) and controls (CON), to identify novel regulatory mechanisms of sarcopenia in ALD. We generated 13 untargeted datasets, including chromosomal conformation, RNA sequencing, proteomics, phosphoproteomics, acetylomics, and metabolomics and conducted a comprehensive analysis using upset plots and feature extraction-based approaches. The most altered molecular interactions were experimentally validated in different models using immunoblots, redox measurements, imaging methods, and measures of senescence associated molecular phenotype (SAMP). Redox ratio was reversed using mitochondrial targeted Lactobacillus brevis NADH oxidase (MitoLbNOX). Results. Enrichments in mitochondrial oxidative function, protein synthesis, and senescence pathways were identified. Multiomics analyses were consistent with the known effects of hypoxia inducible factor 1 (HIF1) that inhibits mitochondrial oxidative dysfunction and promotes skeletal muscle senescence. Pertubrations in genes in the nicotinamide dinucleotide-related pathways including sirtuin signaling, known regulators of senescence, was also noted with ethanol treatment. Experimentally, HIF1 protein was stabilized in myotubes and muscle tissue without cellular hypoxia. Mitochondrial electron transport chain protein expression was less in murine myotubes and hiPSCm with lower redox ratio, less expression of sirtuins, and increased acetylation of mitochondrial proteins. SAMP noted in multiple models in response to ethanol exposure and reversing redox ratio with MitoLbNOX prevented HIF1a stabilization and SAMP in murine myotubes. Conclusions. Our integrated multiomics analyses combined with complementary experimental validation, identify HIF1a stabilization with accelerated skeletal muscle post-mitotic senescence as novel mechanisms of sarcopenia in ALD, highlighting the complex interactions that result in mitochondrial dysfunction with persistent and progressive sarcopenia in ALD.
2025-06-13 | PXD057651 | Pride
Project description:To gain comprehensive and accurate system biological information, we developed a multiomics analytical method that integrated metabolomics and proteomics, named Windows Scanning Multiomics (WSM).
2023-12-18 | PXD046554 | Pride
Project description:To gain comprehensive and accurate system biological information, we developed a multiomics analytical method that integrated metabolomics and proteomics, named Windows Scanning Multiomics (WSM).
2023-12-18 | PXD046533 | Pride