Cholesterol depletion increases expression of autophagy-related genes in mink lung Mv1Lu cells
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ABSTRACT:
PROVIDER: PRJNA745440 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15097300.fastq.gz | Fastqsanger.gz | |||
| SRR15097301.fastq.gz | Fastqsanger.gz | |||
| SRR15097302.fastq.gz | Fastqsanger.gz | |||
| SRR15097297.fastq.gz | Fastqsanger.gz | |||
| SRR15097298.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: Employ next generation sequencing (NGS) to study the transcriptomic response to prolonged reduction in the cholesterol level, with emphasis on autophagy-related genes. Methods: Mv1Lu cells were subjected (or not; control) to cholesterol depletion (16 h, with lovastatin and mevalonate in the presence of lipoprotein deficient serum (LPDS), resulting in 30% reduction in the level of free cholesterol). mRNA profiles were generated by deep sequencing, in triplicates, using Illumina NextSeq500. See methods and protocols for details regarding downstream bioinformatic analysis. Results: Using an optimized data analysis workflow sequencing data from lung samples and identified that cholesterol depletion resulted in 2844 and 2822 genes with significantly increased or reduced expression, respectively. The set of differentially expressed genes was significantly enriched with functional annotations relating to cholesterol metabolic regulation and autophagy. These results were correlated with the upregulation of autophagy in biochemical studies. Conclusions: Mild reduction in the cholesterol level leads to a highly significant increase in the expression of multiple autophagy-related genes. The autophagy genes whose expression was modified by cholesterol depletion were scattered onto multiple steps of the autophagy process, and suggested a mainly positive regulation of autophagy by statin treatment.
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Project description:During autophagy, cytosolic cargo is sequestered into double-membrane vesicles called autophagosomes. The origin and identity of the membranes that form the autophagosome remain to be fully characterized. Here, we investigated the role of cholesterol in starvation-induced autophagy and identify a role for the ER-localized cholesterol transport protein GRAMD1C in the regulation of autophagy and mitochondrial function. We demonstrate that cholesterol depletion leads to a rapid induction of autophagy, possibly caused by a corresponding increased abundance of curved autophagy membranes. We further show that GRAMD1C is a negative regulator of starvation-induced autophagy. Similar to its yeast orthologue, GRAMD1C is recruited to mitochondria through its GRAM domain. Additionally, we find that GRAMD1C depletion leads to increased mitochondrial cholesterol accumulation and mitochondrial oxidative phosphorylation. Finally, we demonstrate that expression of GRAM family genes is linked to clear cell renal carcinoma survival, highlighting the pathophysiological relevance of cholesterol transport proteins.
2022-10-19 | PXD027502 | Pride
Project description:During autophagy, cytosolic cargo is sequestered into double-membrane vesicles called autophagosomes. The origin and identity of the membranes that form the autophagosome remain to be fully characterized. Here, we investigated the role of cholesterol in starvation-induced autophagy and identify a role for the ER-localized cholesterol transport protein GRAMD1C in the regulation of autophagy and mitochondrial function. We demonstrate that cholesterol depletion leads to a rapid induction of autophagy and a corresponding increased abundance of curved autophagy membranes. We further show that GRAMD1C is a negative regulator of starvation-induced autophagy. Similar to its yeast orthologue, GRAMD1C is recruited to mitochondria through its GRAM domain. Additionally, we find that GRAMD1C depletion leads to increased mitochondrial cholesterol accumulation and mitochondrial oxidative phosphorylation. Finally, we demonstrate that expression of GRAM family genes is linked to clear cell renal carcinoma survival, highlighting the pathophysiological relevance of cholesterol transport proteins.
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Project description:Lipid rafts are cholesterol-rich cell signaling platforms and their physiological role can be explored by cholesterol depletion. To dress a global picture of transcriptional changes ongoing after lipid raft disruption, we performed whole-genome expression profiling in epidermal keratinocytes, a cell type which synthesizes its cholesterol in situ. We used microarrays to identify transcriptional changes in gene expression of cholesterol-depleted keratinocytes. Cholesterol depletion by methyl-beta-cyclodextrin disrupts the organization of lipid rafts, which are cholesterol- and sphingolipid-rich membrane microdomains. Transcript levels were measured in autocrine confluent cultures of normal human epidermal keratinocytes were either left untreated (Ctrl), cholesterol-depleted for 1h with 7.5mM methyl-beta-cyclodextrin (MBCD), or mock cholesterol-depleted for 1h with 7.5mM cholesterol-charged methyl-beta-cyclodextrin complexes (MBCD/chol) (Mock cholesterol depletion is a suppementary negative control as this treatment does not extract cholesterol from cell membranes). Samples are analysed either immediately after the treatment (R0h) or after recovery times of 1h (R1h) respectively 8h (R8h). in total 9 samples are analysed and no replicates are performed.
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Project description:Lipid rafts are cholesterol-rich cell signaling platforms and their physiological role can be explored by cholesterol depletion. To dress a global picture of transcriptional changes ongoing after lipid raft disruption, we performed whole-genome expression profiling in epidermal keratinocytes, a cell type which synthesizes its cholesterol in situ. We used microarrays to identify transcriptional changes in gene expression of cholesterol-depleted keratinocytes. Cholesterol depletion by methyl-beta-cyclodextrin disrupts the organization of lipid rafts, which are cholesterol- and sphingolipid-rich membrane microdomains.
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Project description:The concept of targeting cholesterol metabolism to treat cancer has been widely tested in clinics but the benefits are modest, calling for a complete understanding of cholesterol metabolism of intratumoral cells. Low cholesterol levels inhibit T-cell proliferation and cause autophagy mediated apoptosis, particularly for cytotoxic T cells. In the tumor microenvironment, oxysterols mediate reciprocal alterations of the LXR and SREBP2 pathways to cause cholesterol deficiency of T cells, subsequently leading to aberrant metabolic and signaling pathways that drive T cell exhaustion/dysfunction. LXR depletion in CAR-T cells led to improved antitumor function against solid tumor.
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Project description:American mink genome sequencing
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Project description:Metabolic profiling in wild type and autophagy-deficient human embryonic stem cell (hESC)-derived neurons after 3 weeks of neuronal differentiation.
Autophagy is a homeostatic process critical for cellular survival, and its malfunction is implicated in myriad human diseases including neurodegeneration. Loss of autophagy contributes to cytotoxicity and tissue degeneration, but the mechanistic understanding of this phenomenon remains elusive. Here we have generated autophagy-deficient human embryonic stem cells (hESCs), from which we have established human neuronal platform to investigate how loss of autophagy affects neuronal survival. ATG5 deficient neurons exhibit basal cytotoxicity accompanied by metabolic defects. Depletion of nicotinamide adenine dinucleotide (NAD) due to hyperactivation of NAD-consuming enzymes is found to trigger cell death via mitochondrial depolarisation in ATG5 deficient neurons. Boosting intracellular NAD levels improve cell viability by restoring mitochondrial bioenergetics and proteostasis in ATG5 deficient neurons. Our findings elucidate a mechanistic link between autophagy deficiency and neuronal cell death that can be targeted for therapeutic interventions in neurodegenerative and lysosomal storage diseases associated with autophagic defect.
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