Transcriptome Analysis of the Mesenteric Adipose and Liver Reveals Novel Mechanisms by Which Prenatal Alcohol Exposure Contributes to Worse Stroke Outcome
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ABSTRACT:
PROVIDER: PRJNA897850 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR22177200_1.fastq.gz | Fastqsanger.gz | |||
| SRR22177200_2.fastq.gz | Fastqsanger.gz | |||
| SRR22177201_1.fastq.gz | Fastqsanger.gz | |||
| SRR22177201_2.fastq.gz | Fastqsanger.gz | |||
| SRR22177202_1.fastq.gz | Fastqsanger.gz |
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Project description:Prenatal alcohol exposure (PAE) is linked to elevated risk for systemic adult-onset diseases like hypertension, impaired glucose and immune regulation, and in animal models, to impaired recovery from acute onset diseases like cerebrovascular ischemic stroke. Recent evidence suggests that the gastrointestinal system rapidly becomes dysbiotic following cerebrovascular stroke, resulting in systemic inflammation. We hypothesized that a history of PAE would modify the systemic effects of stroke, and transduce exposure-dependent transcriptomic changes in downstream sentinel tissues of the enteric portal circulation that have previously been linked to biobehavioral outcomes in rodent PAE models. Pregnant Sprague Dawley rats were exposed to repeated episodes of vaporized ethanol or room air from gestational day 8 to 19. At 5 months, progeny from each treatment condition were subjected to unilateral endothelin-1 induced occlusion of the middle cerebral artery and outcomes evaluated after 2 days while other progeny stayed stroke-naïve. Stroke induced disabilities were assessed by behavioral assays (adhesive removal, Vibrissae evoked fore-limb placement, circling) and infarct size. The mesenteric adipose tissue and liver transcriptomes were assessed by sequencing, from age-matched stroke-exposed and stroke-naïve offspring. In stroke-naïve animals, pathway analysis identified rRNA processing as downregulated and citric acid cycle as upregulated in mesenteric adipose. Weighted gene correlation network analysis (WGCNA) identified, in the liver of stoke-naïve animals, a moderate but significant correlation between PAE status and necroptosis, a proinflammatory form of programmed cell death (Pearson’s r=0.554, p<0.05). Two days after a stroke, PAE rats exhibited worse neurological scores compared to controls (p<0.05). WGCNA after stroke identified an adipose gene network associated with B cell differentiation and NF-kappa B signaling as moderately correlated with post-stroke neurological function (Pearson's r=0.52, p=0.05). Post-stroke WGCNA also identified a liver proinflammatory gene network strongly correlated with post-stroke neurological function (Pearson's r=-0.63, p<0.01). PAE persistently alters the transcriptome of afferent tissue targets of enteric circulation in adult rat offspring. Moreover, PAE-linked enteric inflammation is correlated to worse outcomes following cerebrovascular ischemic stroke in adulthood. Enteric disturbances may mediate adverse brain health outcomes due to PAE in adulthood.
2023-08-29 | GSE217173 | GEO
Project description:Background: Maternal high-fat diet (MHFD) has been shown to increase susceptibility to neurological disease in later offspring, but the underlying mechanism is not clear. Fibroblast growth factor 21 (FGF21) has been reported to have a neuroprotective effect in stroke, but its mechanism of action remains unknown. In this study, we investigated the mechanism of the effect of MHFD on stroke in offspring in adulthood and the mechanism by which FGF21 acts on stroke and restores neurological function. Methods: We performed transcriptome sequencing analysis on D21 neonatal rats. Bodyweight and blood indicators were recorded in the adult rats after MHFD. FGF21 was administered 7 h after photochemical modeling twice a day for three consecutive days. Results: We found numerous mRNA changes between the MHFD group and a normal maternal diet (MND) group at D21, including genes related to astrocyte and PI3K/Akt pathways. The body weight, blood glucose, and triglycerides of the MHFD offspring were higher, ischemic lesions were larger, the number of activated astrocytes was lower, and the neurological function score was worse than that of the MND group. After FGF21 administration, WB and qPCR analyses showed that astrocytes and the PI3K/Akt pathway were upregulated, while NF-κB and inflammatory cytokines expression were inhibited in stroke and peri-stroke regions. Conclusion: Taken together, we conclude that MHFD alters the characteristics of astrocytes and other transcriptome changes in their offspring, leading to a worse prognosis of stroke, while FGF21 plays a neuroprotective role by inhibiting NF-κB and inflammatory factors and activating the PI3K/Akt pathway and activating more astrocytes in the MND group than the MHFD group.
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Project description:Ischemic stroke is one of the leading causes of disability and mortality worldwide, recognizing aging as a prominent risk factor and determinant of dismal outcome. Aging is known to lead to overall frailty due to multifactorial changes, but pathogenic mechanisms underlying poor outcome remain unclear. Here we show that deterioration in elderly stroke is preceded by neutrophil accumulation and clogging in the ischemic brain microcirculation leading to a worse no-reflow phenomenon. With high-dimensional single-cell profiling over time of the brain's, blood's, and bone marrow's immune response, we could delineate after stroke four main neutrophil clusters in the blood whose quantitative and temporal dynamic of release is deranged in the bone marrow of the old. In the elderly, stroke triggers an early surge in the blood of the CD62Llo neutrophil subset characterized by a signature of bone marrow proximity, senescence, and oxidative stress. Functionally, transfer of this neutrophil subset displaying prominent thrombogenic features in young stroke mice leads to increased clogging of the ischemic brain microcirculation, worse no-reflow and outcome. Interrogating the blood leukocyte landscape of a large human stroke cohort with extensive single-cell proteome analyses, we confirmed that older stroke patients display a similar precocious accumulation of blood CD62Llo neutrophil subset, worse reperfusion and outcome. Our results demonstrate how age-related alterations in the process of neutrophil differentiation and release from the bone marrow have a relevant pathogenic role in the major cerebrovascular disorder affecting the world population, that unleash emergency granulopoiesis.
2023-05-16 | GSE174438 | GEO
Project description:Background and Purpose The neurological course after stroke is highly variable and is determined by demographic, clinical, and genetic factors. However, other heritable factors such as epigenetic DNA methylation could play a role in neurological changes after stroke. Methods We performed a three-stage epigenome-wide association study (EWAS) to evaluate DNA methylation associated with the difference between the National Institutes of Health Stroke Scale (NIHSS) at baseline and at discharge (ΔNIHSS) in ischemic stroke patients. DNA methylation data in the Discovery (n = 643) and Replication (n = 62) Cohorts were interrogated with the 450K and EPIC BeadChip. Nominal CpG-sites from the Discovery (p-value < 10-06) were also evaluated in a meta-analysis of the Discovery and Replication cohorts, using a random-fixed effect model. Specific cell type methylation was assessed using EpiDISH. We integrated the methylation data with 1305 plasma protein expression levels measured by SOMAscan and measured RNA expression with RT-PCR in a subgroup of 13 subjects. Results The meta-analysis revealed an epigenome-wide significant association in EXOC4 (p-value = 8.4x10-08) and in MERTK (p-value = 1.56x10-07). Only the methylation in EXOC4 was also associated in the Discovery and in the Replication cohort (p-value = 1.14x10-06 and p-value = 1.3x10-02, respectively). EXOC4 methylation negatively correlated with the long-term outcome (coefficient = -5.89) and showed a tendency towards a decrease in EXOC4 expression (rho = -0.469, p-value = 0.091). Pathway enrichment from the meta-analysis revealed significant associations related with the exocytic process. Seventy-nine plasma proteins were differentially expressed in association with EXOC4 methylation. Pathway analysis of these proteins showed an enrichment in Natural Killer cell activation. Conclusions DNA methylation of EXOC4 is associated with a worse neurological course after stroke. Pathway analysis suggests that the exocytic pathway could be a potential biological mechanism underlying this association. Background and Purpose The neurological course after stroke is highly variable and is determined by demographic, clinical, and genetic factors. However, other heritable factors such as epigenetic DNA methylation could play a role in neurological changes after stroke. Methods We performed a three-stage epigenome-wide association study (EWAS) to evaluate DNA methylation associated with the difference between the National Institutes of Health Stroke Scale (NIHSS) at baseline and at discharge (ΔNIHSS) in ischemic stroke patients. DNA methylation data in the Discovery (n = 643) and Replication (n = 62) Cohorts were interrogated with the 450K and EPIC BeadChip. Nominal CpG-sites from the Discovery (p-value < 10-06) were also evaluated in a meta-analysis of the Discovery and Replication cohorts, using a random-fixed effect model. Specific cell type methylation was assessed using EpiDISH. We integrated the methylation data with 1305 plasma protein expression levels measured by SOMAscan and measured RNA expression with RT-PCR in a subgroup of 13 subjects. Results The meta-analysis revealed an epigenome-wide significant association in EXOC4 (p-value = 8.4x10-08) and in MERTK (p-value = 1.56x10-07). Only the methylation in EXOC4 was also associated in the Discovery and in the Replication cohort (p-value = 1.14x10-06 and p-value = 1.3x10-02, respectively). EXOC4 methylation negatively correlated with the long-term outcome (coefficient = -5.89) and showed a tendency towards a decrease in EXOC4 expression (rho = -0.469, p-value = 0.091). Pathway enrichment from the meta-analysis revealed significant associations related with the exocytic process. Seventy-nine plasma proteins were differentially expressed in association with EXOC4 methylation. Pathway analysis of these proteins showed an enrichment in Natural Killer cell activation. Conclusions DNA methylation of EXOC4 is associated with a worse neurological course after stroke. Pathway analysis suggests that the exocytic pathway could be a potential biological mechanism underlying this association.
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2011-02-09 | E-GEOD-27005 | biostudies-arrayexpress