LINC00894 regulated cerebral ischemia/reperfusion injury by stabilizing EIF5 and facilitating ATF4-mediated induction of FGF21 and ACOD1
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ABSTRACT:
PROVIDER: PRJNA1117031 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29195269_1.fastq.gz | Fastqsanger.gz | |||
| SRR29195269_2.fastq.gz | Fastqsanger.gz | |||
| SRR29195270_1.fastq.gz | Fastqsanger.gz | |||
| SRR29195270_2.fastq.gz | Fastqsanger.gz | |||
| SRR29195271_1.fastq.gz | Fastqsanger.gz |
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Project description:Long intergenic non-coding RNA 894 (LINC00894) modulates cancer cell proliferation and drug resistance in several tissue types. However, its role in brain is still unclear. Using RNA-pull down combined with mass spectrometry and RNA binding protein immunoprecipitation, EIF5 was identified to physically interact with LINC00894. Furthermore, LINC00894 knockdown decreased EIF5 protein expression, whereas LINC00894 overexpression increased EIF5 protein expression in cultured cells. Additionally, LINC00894 affected the ubiquitination modification of EIF5. Adeno-associated virus (AAV) mediated LINC00894 overexpression in the brains of transient middle cerebral artery occlusion reperfusion (MCAO/R) mice and rats and inhibited the expression of activated caspase-3. Meanwhile, LINC00894 knockdown increased in the oxygen–glucose deprivation and reoxygenation (OGD/R) in vitro models, whereas its overexpression decreased apoptotic cells and expression of activated caspase-3. Further, LINC00894 overexpression was revealed to increase, whereas its knockdown shortened ATF4 protein half-life. LINC00894 knockdown also decreased the expression of glutamate-cysteine ligase catalytic subunit (GCLC) and ATF4, downregulated glutathione (GSH), and the ratio of GSH to oxidized GSH (GSH: GSSG) in vitro. RNA-seq analysis combined with qRT-PCR and immunoblot showed overexpression of LINC0084 upregulated ATF4, thereby potentially targeting fibroblast growth factor 21 (FGF21) and aconitate decarboxylase 1 (ACOD1) in the MCAO/R model. Finally, we revealed that ATF4 regulated FGF21 and ACOD1 expression by directly binding to promoters; and ectopic overexpression of FGF21 or ACOD1 in LINC00894 knockdown cells decreased activated caspase-3 expression in the OGD/R model. Our results indicated that LINC00894 regulated cerebral ischemia injury by stabilizing EIF5 and facilitating EIF5-ATF4-dependent induction of FGF21 and ACOD1
2024-06-06 | GSE268399 | GEO
Project description:The non-coding RNA LINC00894 modulates tumor proliferation and drug resistance. However, its role in brain is still unclear. Using RNA-pull down combined with mass spectrometry and RNA binding protein immunoprecipitation, EIF5 was identified to interact with LINC00894. Furthermore, LINC00894 knockdown decreased EIF5 protein expression, whereas LINC00894 overexpression increased EIF5 protein expression in SH-SY5Y and BE(2)-M17 (M17) neuroblastoma cells. Additionally, LINC00894 affected the ubiquitination modification of EIF5. Adeno-associated virus (AAV) mediated LINC00894 overexpression in the brain inhibited the expression of activated Caspase-3, while increased EIF5 protein level in rats and mice subjected to transient middle cerebral artery occlusion reperfusion (MCAO/R). Meanwhile, LINC00894 knockdown increased the number of apoptotic cells and expression of activated Caspase-3, and its overexpression decreased them in the oxygen-glucose deprivation and reoxygenation (OGD/R) in vitro models. Further, LINC00894 was revealed to regulated ATF4 protein expression in condition of OGD/R and normoxia. LINC00894 knockdown also decreased the expression of glutamate-cysteine ligase catalytic subunit (GCLC) and ATF4, downregulated glutathione (GSH), and the ratio of GSH to oxidized GSH (GSH: GSSG) in vitro. By using RNA-seq combined with qRT-PCR and immunoblot, we identified that fibroblast growth factor 21 (FGF21) and aconitate decarboxylase 1 (ACOD1), as the ATF4 target genes were regulated by LINC00894 in the MCAO/R model. Finally, we revealed that ATF4 transcriptionally regulated FGF21 and ACOD1 expression; ectopic overexpression of FGF21 or ACOD1 in LINC00894 knockdown cells decreased activated Caspase-3 expression in the OGD/R model. Our results demonstrated that LINC00894 regulated cerebral ischemia injury by stabilizing EIF5 and facilitating EIF5-ATF4-dependent induction of FGF21 and ACOD1.
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Project description:Mitochondrial integrated stress response emerged as a major adaptive pathway to respiratory chain deficiency, but tissue-specifics of its regulation or how it adapts to different levels of mitochondrial dysfunction are largely unknown. Here we report that diverse levels of mitochondrial cardiomyopathy activate mitoISR, including high production of FGF21, a cytokine with both paracrine and endocrine function, shown to be induced by respiratory chain dysfunction. Remarkably, although being fully dispensable for the cell-autonomous and systemic responses to severe mitochondrial cardiomyopathy, in the conditions of mild-to-moderate cardiac OXPHOS dysfunction, FGF21 regulates a portion of the mitoISR. In the absence of FGF21, a large part of the metabolic adaptation to mitochondrial dysfunction (one-carbon metabolism, transsulfuration and serine and proline biosynthesis) is strongly blunted, independent of the primary mitoISR activator ATF4. Collectively, our work highlights the complexity of mitochondrial stress responses by revealing the importance of the tissue-specificity and dose-dependency of the mitoISR.
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Project description:Enhanced osteoclast-mediated bone erosion is a prominent hallmark of rheumatoid arthritis. Emerging evidence suggests that this process is facilitated by metabolic dysregulation of osteoclasts. The mitochondrial enzyme aconitate decarboxylase 1 (Acod1, also known as immune responsive gene 1 [Irg1]) serves as a mediator between the metabolic condition and the functional state of different types of cells. Acod1-deficient mice are characterized by enhanced osteoclast differentiation and bone erosion in an inflammatory arthritis model, while therapeutic treatment with the itaconate-derivative 4-octyl-itaconate (4-OI) alleviates the disease phenotype in experimental arthritis. To ascertain the influence of the Acod1-itaconate axis on the genomic transcriptional network of osteoclasts, we performed a whole transcriptome RNA sequencing analysis with fully differentiated osteoclasts from WT and Acod1-deficient mice that were cultured in the presence or absence of 4-OI.
2024-07-15 | GSE237504 | GEO
Project description:FGF21 is a novel secreted protein with robust anti-diabetic, anti-obesity, and anti-atherogenic activities in preclinical species. In the current study, we investigated the signal transduction pathways downstream of FGF21 following acute administration of the growth factor to mice. Focusing on adipose tissues, we identified FGF21-mediated downstream signaling events and target engagement biomarkers. Specifically, RNA profiling of adipose tissues and phosphoproteomic profiling of adipocytes, following FGF21 treatment revealed several specific changes in gene expression and post-translational modifications, specifically phosphorylation, in several relevant proteins. Affymetrix microarray analysis of white adipose tissues isolated from both C57BL/6 (fed either regular chow or HFD) and db/db mice identified over 150 robust potential RNA transcripts and over 50 potential secreted proteins that were changed greater than 1.5 fold by FGF21 acutely. Phosphoprofiling analysis identified over 130 phosphoproteins that were modulated greater than 1.5 fold by FGF21 in 3T3-L1 adipocytes. Bioinformatic analysis of the combined gene and phosphoprotein profiling data identified a number of known metabolic pathways such as glucose uptake, insulin receptor signaling, Erk/Mapk signaling cascades, and lipid metabolism. Moreover, a number of novel events with hitherto unknown links to FGF21 signaling were observed at both the transcription and protein phosphorylation levels following treatment. We conclude that such a combined "omics" approach can be used not only to identify robust biomarkers for novel therapeutics but can also enhance our understanding of downstream signaling pathways; in the example presented here, novel FGF21-mediated signaling events in adipose tissue have been revealed that warrant further investigation. Three mouse strains (C57BL6 on chow diet, C57BL6 on high fat diet, and db/db on chow diet) were treated with either vehicle, wild-type FGF21, or pegylated FGF21 acutely or for several days and three white adipose tissues (IWAT, EWAT, RPWAT) and brown adipose tissue (BAT) were profiled on custom Affymetrix microarrays. The primary goal was to identify robust and consistent acute target engagement biomarkers of FGF21 activation in white adipose tissues.
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Project description:To elucidate the signalling network responsible for mediating the effects of FGF21, we quantified the dynamic phosphoproteome of adipocytes following acute exposure to this hormone. A major FGF21-regulated signalling node was mTORC1/S6K. In contrast to insulin, we find that FGF21 activates mTORC1 via MAPK signalling rather than through the canonical PI3K/AKT pathway. This study provides a systems view of FGF21 signalling and reveals a new role for mTORC1 in maintaining nutrient homeostasis.
2016-08-15 | PXD003631 | Pride
Project description:Mitochondrial integrated stress response emerged as a major adaptive pathway to respiratory chain deficiency, but tissue-specifics of its regulation or how it adapts to different levels of mitochondrial dysfunction are largely unknown. Here we report that diverse levels of mitochondrial cardiomyopathy activate mitoISR, including high production of FGF21, a cytokine with both paracrine and endocrine function, shown to be induced by respiratory chain dysfunction. Remarkably, although being fully dispensable for the cell-autonomous and systemic responses to severe mitochondrial cardiomyopathy, in the conditions of mild-to-moderate cardiac OXPHOS dysfunction, FGF21 regulates a portion of the mitoISR. In the absence of FGF21, a large part of the metabolic adaptation to mitochondrial dysfunction (one-carbon metabolism, transsulfuration and serine and proline biosynthesis) is strongly blunted, independent of the primary mitoISR activator ATF4. Collectively, our work highlights the complexity of mitochondrial stress responses by revealing the importance of the tissue-specificity and dose-dependency of the mitoISR.
2022-02-04 | GSE195947 | GEO
Project description:Fibroblast growth factor 21 (FGF21) is a key metabolic regulator which was recently discovered as stress-induced myokine and common denominator of muscle mitochondrial disease. However, its precise function and pathophysiological relevance remains unknown. Here we demonstrate that white adipose tissue (WAT) is the major target of muscle mitochondrial stress-induced FGF21. Strikingly, substantial browning and metabolic remodeling of subcutaneous WAT, together with the reduction of circulating triglycerides and cholesterol are fully FGF21 dependent. Unexpectedly and in contrast to prior expectations, we found a negligible role of FGF21 in muscle stress-related improved glycemic control, obesity resistance and hepatic lipid homeostasis. Furthermore, we show that the protective muscle mitohormesis and metabolic stress adaptation does not require FGF21 action. Taken together, our data imply that although FGF21 drives WAT remodeling, this effect and FGF21 as stress hormone per se may not be essential for the adaptive response under muscle mitochondrial stress conditions. Wildtype male mice and FGF21-knockout male mice, together with muscle specific UCP1-transgenic male animals, and double cross of FGF21-KO with UCP1-Tg male mice, were kept on a standardized low fat diet for 40 weeks. After sacrifice, subcutaneous white adipose tisseu (scWAT) was rapidly removed, weighed, and snap frozen in liquid nitrogen and used for RNA isolation and whole genome gene expression microarray hybridisation using Agilent arrays.
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