Galectin3: a novel biomarker of glycogen storage disease type III
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1138737 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29917712.fastq.gz | Fastqsanger.gz | |||
| SRR29917713.fastq.gz | Fastqsanger.gz | |||
| SRR29917714.fastq.gz | Fastqsanger.gz | |||
| SRR29917715.fastq.gz | Fastqsanger.gz | |||
| SRR29917716.fastq.gz | Fastqsanger.gz |
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Project description:Glycogen storage disease type III (GSDIII) is a rare genetic disease caused by mutations in the AGL gene, resulting in glycogen debranching enzyme (GDE) deficiency. There is currently no cure. Among various symptoms, skeletal muscle impairment represents a key target for the development of therapies. Identifying reliable biomarkers is crucial for evaluating new therapies, yet muscle-specific biomarkers for GSDIII are lacking. In this study, we generated GSDIII skeletal muscle cells derived from human-induced pluripotent stem cells that recapitulate the glycogen accumulation phenotype. A comparative gene expression analysis was carried out using RNA sequencing to identify novel biomarkers. Our results reports a significant overexpression of galectin-3 in both human and mouse models and patient biopsies, and a significant decrease in mice treated by an AAV gene therapy. Together, our results propose galectin-3 as a biomarker to assess therapeutic efficacy and GSDIII pathological monitoring in the muscle.
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Project description:Glycogen and lipid are major storage forms of energy that are tightly regulated by hormones and metabolic signals. Here, we evaluate the role of the glycogenic scaffolding protein PTG/R5 in energy homeostasis. We demonstrate that feeding mice a high-fat diet (HFD) increases hepatic glycogen, corresponding to increased PTG levels, increased activity of the mechanistic target of rapamycin complex 1 (mTORC1) and induced expression of sterol regulatory element binding protein 1c (SREBP1c). PTG promoter activity was increased by activation of mTORC1 and SREBP1, and PTG and glycogen levels were augmented in mice and cells in which mTORC1 is constitutively active. HFD-dependent increases in hepatic glycogen were prevented by deletion of the PTG gene in mice. Interestingly, PTG knockout mice fed HFD exhibited improved liver steatosis and decreased lipid levels in muscle, in coordination with decreased glycogen, suggesting possible crosstalk between glycogen and lipid stores in the overall control of energy metabolism. Together, these data suggest that transcriptional regulation of PTG by dietary and nutritional cues has profound effects on energy storage and metabolism.fi
2014-06-13 | GSE45319 | GEO
Project description:Glycogen and lipid are major storage forms of energy that are tightly regulated by hormones and metabolic signals. Here, we evaluate the role of the glycogenic scaffolding protein PTG/R5 in energy homeostasis. We demonstrate that feeding mice a high-fat diet (HFD) increases hepatic glycogen, corresponding to increased PTG levels, increased activity of the mechanistic target of rapamycin complex 1 (mTORC1) and induced expression of sterol regulatory element binding protein 1c (SREBP1c). PTG promoter activity was increased by activation of mTORC1 and SREBP1, and PTG and glycogen levels were augmented in mice and cells in which mTORC1 is constitutively active. HFD-dependent increases in hepatic glycogen were prevented by deletion of the PTG gene in mice. Interestingly, PTG knockout mice fed HFD exhibited improved liver steatosis and decreased lipid levels in muscle, in coordination with decreased glycogen, suggesting possible crosstalk between glycogen and lipid stores in the overall control of energy metabolism. Together, these data suggest that transcriptional regulation of PTG by dietary and nutritional cues has profound effects on energy storage and metabolism.fi RNA-Seq analysis was used to characterize hepatic diet-associated gene expression changes between wild-type and PTG KO mice. Mice were maintained on a normal chow diet or a high-fat diet as indicated. 2-3 biological replicates per genotype/diet.
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Project description:Glycogen is the largest soluble cytosolic macromolecule and considered as the principal storage form of glucose. Cancer cells generally increase their glucose consumption and rewire their metabolism towards aerobic glycolysis to promote growth. Here we report that glycogen accumulation is a key initiating oncogenic event and essential for malignant transformation. RNA-sequencing analysis reveals that G6PC, an enzyme catalyzing the last step of glycogenolysis, is frequently downregulated to augment glucose storage in pro-tumor cells. Accumulated glycogen undergoes liquid-liquid phase separation undergoes liquid-liquid phase separation, which results in the assembly of the laforin-Mst1/2 complex and consequently traps Hippo kinases Mst1/2 in glycogen liquid droplets to relieve their inhibition on Yap. Moreover, G6PC or another glycogenolysis enzyme PYGL deficiency in both human and mice result in glycogen storage disease with enlarged liver size and cancer development, phenocopying Hippo deficiency. Consistently, elimination of glycogen accumulation abrogates liver enlargement and cancer incidence, whereas increasing glycogen storage accelerates tumorigenesis. Thus, we concluded that glycogen not only provides nutrition and energy to the cells but also functions as a key initiating oncogenic metabolite, which physically blocks Hippo signaling through glycogen phase separation to augment pro-tumor cell initiation and progression.
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Project description:The transition from a fasted to a fed state is associated with extensive transcriptional remodeling in hepatocytes facilitated by hormonal- and nutritional-regulated transcription factors. Here, we use a liver-specific glucocorticoid receptor (GR) knock-out (L-GRKO) model and primary hepatocytes to investigate the temporal expression of GR target genes in response to feeding. Interestingly, in addition to the well described fasting-regulated genes, we identify a subset of hepatic feeding-induced genes that requires GR for full expression, adding new insights to hepatic GR function. The GR-controlled feeding-induced genes include Gck encoding the glucokinase, which is important for hepatic glucose uptake, utilization and storage. We show that insulin and glucocorticoids cooperatively regulate Gck expression in primary hepatocytes in a GR-dependent manner. ChIP-seq experiments suggest direct GR regulation of Gck by GR occupancy of the promoter and two putative regulatory regions near the Gck gene (Gck -1kb and Gck -4.6kb). Enhancer-reporter assays and CRISPRi suggest that the 4.6kb upstream GR binding site is a functional Gck enhancer. L-GRKO blunts preprandial and early postprandial Gck expression and GR disruption ultimately affects early postprandial hepatic glucose uptake, phosphorylation and glycogen storage. Collectively, our study demonstrates how GR is positively involved in the hepatic feeding response exemplified in the direct regulation of the feeding-induced transcription of glucokinase, important for hepatic glucose metabolism.
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