Mapping the daily rhythmic transcriptome in the diabetic retina
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA976271 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24739200_1.fastq.gz | Fastqsanger.gz | |||
| SRR24739200_2.fastq.gz | Fastqsanger.gz | |||
| SRR24739201_1.fastq.gz | Fastqsanger.gz | |||
| SRR24739201_2.fastq.gz | Fastqsanger.gz | |||
| SRR24739202_1.fastq.gz | Fastqsanger.gz |
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Project description:The mammalian retina contains an endogenous circadian clock system, located in various cell types. This system enables timing of a broad range of essential retinal functions to anticipate daily changes in environmental lighting conditions. Furthermore, the circadian clocks appear to promote retinal health. A leading cause of blindness in developed countries is diabetic retinopathy. While it is clear that diabetes affects the master clock and its circadian output in the SCN, the effect of diabetic retinopathy on the retinal clock system is unknown. To investigate the influence of diabetic retinopathy on circadian regulation of the retina at a genome-wide level, microarray analysis was used to compare retinal transcriptomes between light- and dark-adapted non-diabetic and diabetic mice.
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Project description:The ocular circadian clock has been thought to be regulated primarily by environmental light. In many peripheral tissues, however, circadian clocks are influenced by temporal information conveyed by adrenal glucocorticoids, while glucocorticoid-dependent regulation of the eye clock, a light-receptive organ, has remained unclear. To investigate this mechanism, we generated retina-specific Nr3c1 (glucocorticoid receptor; GR) knockout mice by crossing Chx10-Cre mice, in which Cre-recombinase is driven by the Chx10 promoter expressed in the developing optic cup, with Nr3c1 flox/flox mice. Using these mice, we performed time-course tissue collection under constant dark conditions followed by time-series RNA-seq analysis. The analysis showed that many rhythmic genes detected in control retina were lost in retina-specific Nr3c1-deficient mice, suggesting that glucocorticoid signaling contributes to rhythmic retinal gene expression.
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Project description:The ocular circadian clock has been thought to be regulated primarily by environmental light. In many peripheral tissues, however, circadian clocks are influenced by temporal information conveyed by adrenal glucocorticoids, while glucocorticoid-dependent regulation of the eye clock, a light-receptive organ, has remained unclear. To investigate this mechanism, we generated retina-specific Nr3c1 (glucocorticoid receptor; GR) knockout mice by crossing Chx10-Cre mice, in which Cre-recombinase is driven by the Chx10 promoter expressed in the developing optic cup, with Nr3c1 flox/flox mice. Using these mice, we performed time-course tissue collection under light-dark conditions followed by time-series RNA-seq analysis. The analysis showed that many rhythmic genes detected in control retina were lost in retina-specific Nr3c1-deficient mice, suggesting that glucocorticoid signaling contributes to rhythmic retinal gene expression.
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Project description:Pericyte loss is an early and critical event in the pathogenesis of diabetic retinopathy (DR), yet the molecular mechanisms underlying pericyte dysfunction remain incompletely understood. Using single-cell RNA sequencing, we generated a retinal cellular overview comprising 37,982 cells from diabetic and non-diabetic mice. We identified a previously unrecognized pericyte subpopulation defined by high expression of pituitary tumor transforming gene 1 (PTTG1), which was enriched in diabetic retina. Functional studies demonstrated that CRISPR/Cas9- or siRNA-mediated silencing of PTTG1 restored pericyte stability and barrier-supporting function under high glucose stress. In vivo, PTTG1 silencing via viral or pericyte-specific AAV delivery improved retinal vascular integrity and reduced retinal vascular dysfunction in diabetic mice. Integrated transcriptomic and metabolomic profiling revealed that PTTG1 silencing reprogrammed metabolism, modulating glycolytic flux and attenuating oxidative stress.
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Project description:Hepatic daily rhythms are coordinated by feeding and the molecular circadian clock, ensuring metabolic homeostasis. Disrupted feeding schedules promote circadian misalignment and metabolic disease but the underlying mechanisms remain unknown. Post-translational modifications have emerged as key regulators of circadian metabolic outputs. In this framework, mitochondria constitute a central hub, integrating metabolic rhythms, feeding cycles and the circadian clock. Here, we show that the mitochondrial enzyme Acyl-CoA-synthetase-family-member-3 (ACSF3) oscillates in phase with different feeding schedules to drive rhythmic lysine-malonylation and coordinate daily hepatic metabolism. Hepatic ACSF3 knockdown affected lysine-malonylation rhythms, decreased fasting glycemia, insulin sensitivity and AKT phosphorylation. It also shifted lipid oxidation from mitochondria to peroxisomes, enhanced de novo lipogenesis and triglyceride synthesis, while increasing diurnal autophagy. Integrated multi-omics profiling uncovered specific lysine-malonylation targets in glycolysis, the TCA cycle, fatty-acid oxidation and autophagy. Our findings establish ACSF3 as a critical link between feeding time, protein malonylation, and diurnal liver metabolism.
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Project description:<p> Pericyte loss is an early and critical event in the pathogenesis of diabetic retinopathy (DR), yet the molecular mechanisms underlying pericyte dysfunction remain incompletely understood. Using single-cell RNA sequencing, we generated a retinal cellular overview comprising 18,926 cells from diabetic and non-diabetic mice. We identified a previously unrecognized pericyte subpopulation defined by high expression of pituitary tumor transforming gene 1 (PTTG1), which was enriched in diabetic retina. Functional studies demonstrated that CRISPR/Cas9 or siRNA-mediated silencing of PTTG1 restored pericyte stability and barrier-supporting function under high-glucose stress. In vivo, knockdown of PTTG1 via lentiviral or pericyte-specific AAV delivery improved retinal vascular integrity and reduced retinal vascular function in diabetic mice. Integrated transcriptomic and metabolomic profiling revealed PTTG1 knockdown reprogrammed metabolism by modulating glycolytic flux and attenuating oxidative stress. Furthermore, a therapeutic strategy employing spherical nucleic acid-based siPTTG1 nanocarriers (sTDN-siPTTG1) significantly ameliorated retinal vascular dysfunction in DR model. These findings suggest that PTTG1 is a critical regulator of pericyte metabolic homeostasis and microvascular function in DR, highlighting its translational potential as a therapeutic target for diabetic microvascular complications. </p>
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