Transcriptomic Profiles of Sepsis in the Human Brain.
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ABSTRACT:
SUBMITTER: Bustamante AC
PROVIDER: S-EPMC7124721 | biostudies-literature | 2020 Apr
REPOSITORIES: biostudies-literature
Publications
Transcriptomic Profiles of Sepsis in the Human Brain.
Bustamante Angela C AC Opron Kristopher K Ehlenbach William J WJ Larson Eric B EB Crane Paul K PK Keene C Dirk CD Standiford Theodore J TJ Singer Benjamin H BH
American journal of respiratory and critical care medicine 20200401 7
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Project description:The purpose of this study is to examine the transcriptomic profiles (RNAseq) of post-mortem brain tissue samples from patients who have died of sepsis compared to non-sepsis controls using two analytic approaches. Tissue samples originated from the Adult Changes in Thought study (ACT) brain bank. In order to determine cause of death, hospital charts for 89 ACT subjects who died while hospitalized were reviewed using a structured instrument for diagnosis of sepsis. RNA was extracted from 24 post-mortem parietal cortex tissue samples. RNA sequencing was performed on the 24 samples using Illumina's Hi-Seq platform. Raw data was exported, pre-processed, and analyzed by two methods, differential expression and weighted gene co-expression network analysis (WGCNA). 176 genes were differentially expressed with fold change of > 1.5 and adjusted p < 0.5. The top differentially expressed genes were immune-related. WGCNA reveled 6 modules were significantly correlated with sepsis. Significant nodules were enriched in terms associated with innate immunity, cytokines, DAMPs, synaptic function, ion channel function, neuronal growth, and T-cell signalling among others. These data suggest sepsis is associated with specific transcriptional responses in the human brain. These results provide support for previously identified targets as well as provide evidence to suggest investigation into new targets for mechanistic exploration of sepsis-associated brain injury.
2019-11-26 | GSE135838 | GEO
Project description:Transcriptomic Profiles of Sepsis in the Human Brain
| PRJNA560245 | ENA
Project description:Historically, murine models of inflammation in biomedical research have been shown to minimally correlate with genomic expression patterns from blood leukocytes in humans. In 2019, our laboratory reported an improved surgical sepsis model of cecal ligation and puncture (CLP) that provides additional daily chronic stress (DCS), as well as adhering to the Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS) guidelines. This model phenotypically recapitulates the persistent inflammation, immunosuppression, and catabolism syndrome observed in adult human surgical sepsis survivors. Whether these phenotypic similarities between septic humans and mice are replicated at the circulating blood leukocyte transcriptome has not been demonstrated. Our analysis, in contrast with previous findings, demonstrated that genome-wide expression in our new murine model more closely approximated human surgical sepsis patients, particularly in the more chronic phases of sepsis. Importantly, our new model of murine surgical sepsis with chronic stress did not reflect well gene expression patterns from humans with community-acquired sepsis. Our work indicates that improved preclinical murine sepsis modeling can better replicate both the phenotypic and transcriptomic responses to surgical sepsis, but cannot be extrapolated to other sepsis etiologies. Importantly, these improved models can be a useful adjunct to human-focused and artificial intelligence-based forms of research in order to improve septic patients' morbidity and mortality.
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Project description:BackgroundTranscriptomic studies hold great potential towards understanding the human aging process. Previous transcriptomic studies have identified many genes with age-associated expression levels; however, small samples sizes and mixed cell types often make these results difficult to interpret.ResultsUsing transcriptomic profiles in CD14+ monocytes from 1,264 participants of the Multi-Ethnic Study of Atherosclerosis (aged 55-94 years), we identified 2,704 genes differentially expressed with chronological age (false discovery rate, FDR ≤ 0.001). We further identified six networks of co-expressed genes that included prominent genes from three pathways: protein synthesis (particularly mitochondrial ribosomal genes), oxidative phosphorylation, and autophagy, with expression patterns suggesting these pathways decline with age. Expression of several chromatin remodeler and transcriptional modifier genes strongly correlated with expression of oxidative phosphorylation and ribosomal protein synthesis genes. 17% of genes with age-associated expression harbored CpG sites whose degree of methylation significantly mediated the relationship between age and gene expression (p < 0.05). Lastly, 15 genes with age-associated expression were also associated (FDR ≤ 0.01) with pulse pressure independent of chronological age. Comparing transcriptomic profiles of CD14+ monocytes to CD4+ T cells from a subset (n = 423) of the population, we identified 30 age-associated (FDR < 0.01) genes in common, while larger sets of differentially expressed genes were unique to either T cells (188 genes) or monocytes (383 genes). At the pathway level, a decline in ribosomal protein synthesis machinery gene expression with age was detectable in both cell types.ConclusionsAn overall decline in expression of ribosomal protein synthesis genes with age was detected in CD14+ monocytes and CD4+ T cells, demonstrating that some patterns of aging are likely shared between different cell types. Our findings also support cell-specific effects of age on gene expression, illustrating the importance of using purified cell samples for future transcriptomic studies. Longitudinal work is required to establish the relationship between identified age-associated genes/pathways and aging-related diseases.
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Project description:BACKGROUND:The application of advanced sequencing technologies and improved mass-spectrometry platforms revealed significant changes in gene expression and lipids in Alzheimer's disease (AD) brain. The results so far have prompted further research using "multi-omics" approaches. These approaches become particularly relevant, considering the inheritance of APOEε4 allele as a major genetic risk factor of AD, disease protective effect of APOEε2 allele, and a major role of APOE in brain lipid metabolism. METHODS:Postmortem brain samples from inferior parietal lobule genotyped as APOEε2/c (APOEε2/carriers), APOEε3/3, and APOEε4/c (APOEε4/carriers), age- and gender-matched, were used to reveal APOE allele-associated changes in transcriptomes and lipidomes. Differential gene expression and co-expression network analyses were applied to identify up- and downregulated Gene Ontology (GO) terms and pathways for correlation to lipidomics data. RESULTS:Significantly affected GO terms and pathways were determined based on the comparisons of APOEε2/c datasets to those of APOEε3/3 and APOEε4/c brain samples. The analysis of lists of genes in highly correlated network modules and of those differentially expressed demonstrated significant enrichment in GO terms associated with genes involved in intracellular proteasomal and lysosomal degradation of proteins, protein aggregates and organelles, ER stress, and response to unfolded protein, as well as mitochondrial function, electron transport, and ATP synthesis. Small nucleolar RNA coding units important for posttranscriptional modification of mRNA and therefore translation and protein synthesis were upregulated in APOEε2/c brain samples compared to both APOEε3/3 and APOEε4/c. The analysis of lipidomics datasets revealed significant changes in ten major lipid classes (exclusively a decrease in APOEε4/c samples), most notably non-bilayer-forming phosphatidylethanolamine and phosphatidic acid, as well as mitochondrial membrane-forming lipids. CONCLUSIONS:The results of this study, despite the advanced stage of AD, point to the significant differences in postmortem brain transcriptomes and lipidomes, suggesting APOE allele associated differences in pathogenic mechanisms. Correlations within and between lipidomes and transcriptomes indicate coordinated effects of changes in the proteasomal system and autophagy-canonical and selective, facilitating intracellular degradation, protein entry into ER, response to ER stress, nucleolar modifications of mRNA, and likely myelination in APOEε2/c brains. Additional research and a better knowledge of the molecular mechanisms of proteostasis in the early stages of AD are required to develop more effective diagnostic approaches and eventually efficient therapeutic strategies.
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Project description:BackgroundThe acquisition of reliable tissue-specific RNA sequencing data from human skin biopsy represents a major advance in research. However, the complexity of the process of isolation of specific layers from fresh-frozen human specimen by laser capture microdissection, the abundant presence of skin nucleases and RNA instability remain relevant methodological challenges. We developed and optimized a protocol to extract RNA from layers of human skin biopsies and to provide satisfactory quality and amount of mRNA sequencing data.ResultsThe protocol includes steps of collection, embedding, freezing, histological coloration and relative optimization to preserve RNA extracted from specific components of fresh-frozen human skin biopsy of 14 subjects. Optimization of the protocol includes a preservation step in RNALater® Solution, the control of specimen temperature, the use of RNase Inhibitors and the time reduction of the staining procedure. The quality of extracted RNA was measured using the percentage of fragments longer than 200 nucleotides (DV200), a more suitable measurement for successful library preparation than the RNA Integrity Number (RIN). RNA was then enriched using the TruSeq® RNA Access Library Prep Kit (Illumina®) and sequenced on HiSeq® 2500 platform (Illumina®). Quality control on RNA sequencing data was adequate to get reliable data for downstream analysis.ConclusionsThe described implemented and optimized protocol can be used for generating transcriptomics data on skin tissues, and it is potentially applicable to other tissues. It can be extended to multicenter studies, due to the introduction of an initial step of preservation of the specimen that allowed the shipment of biological samples.
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Project description:Transcriptional effects in circulating leukocytes from mice challenged to peritoneal contamination and infection (PCI) compared to sham (vehicle control). We gratefully acknowledge the BMBF grant for the Center for Sepsis Control and Care (CSCC) for this study
2017-09-01 | GSE36608 | GEO
Project description:IntroductionAlzheimer's disease (AD) is heterogeneous, both clinically and neuropathologically. We investigated whether polygenic risk scores (PRSs) integrated with transcriptome profiles from AD brains can explain AD clinical heterogeneity.MethodsWe conducted co-expression network analysis and identified gene sets (modules) that were preserved in three AD transcriptome datasets and associated with AD-related neuropathological traits including neuritic plaques (NPs) and neurofibrillary tangles (NFTs). We computed the module-based PRSs (mbPRSs) for each module and tested associations with mbPRSs for cognitive test scores, cognitively defined AD subgroups, and brain imaging data.ResultsOf the modules significantly associated with NPs and/or NFTs, the mbPRSs from two modules (M6 and M9) showed distinct associations with language and visuospatial functioning, respectively. They matched clinical subtypes and brain atrophy at specific regions.DiscussionOur findings demonstrate that polygenic profiling based on co-expressed gene sets can explain heterogeneity in AD patients, enabling genetically informed patient stratification and precision medicine in AD.HighlightsCo-expression gene-network analysis in Alzheimer's disease (AD) brains identified gene sets (modules) associated with AD heterogeneity. AD-associated modules were selected when genes in each module were enriched for neuritic plaques and neurofibrillary tangles. Polygenic risk scores from two selected modules were linked to the matching cognitively defined AD subgroups (language and visuospatial subgroups). Polygenic risk scores from the two modules were associated with cognitive performance in language and visuospatial domains and the associations were confirmed in regional-specific brain atrophy data.
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