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Postmortem cardiac tissue maintains gene expression profile even after late harvesting.

ABSTRACT: BACKGROUND: Gene expression studies can be used to help identify disease-associated genes by comparing the levels of expressed transcripts between cases and controls, and to identify functional genetic variants (expression quantitative loci or eQTLs) by comparing expression levels between individuals with different genotypes. While many of these studies are performed in blood or lymphoblastoid cell lines due to tissue accessibility, the relevance of expression differences in tissues that are not the primary site of disease is unclear. Further, many eQTLs are tissue specific. Thus, there is a clear and compelling need to conduct gene expression studies in tissues that are specifically relevant to the disease of interest. One major technical concern about using autopsy-derived tissue is how representative it is of physiologic conditions, given the effect of postmortem interval on tissue degradation. RESULTS: In this study, we monitored the gene expression of 13 tissue samples harvested from a rapid autopsy heart (non-failed heart) and 7 from a cardiac explant (failed heart) through 24 hours of autolysis. The 24 hour autopsy simulation was designed to reflect a typical autopsy scenario where a body may begin cooling to ambient temperature for ~12 hours, before transportation and storage in a refrigerated room in a morgue. In addition, we also simulated a scenario wherein the body was left at room temperature for up to 24 hours before being found. A small fraction (< 2.5%) of genes showed fluctuations in expression over the 24 hr period and largely belong to immune and signal response and energy metabolism-related processes. Global expression analysis suggests that RNA expression is reproducible over 24 hours of autolysis with 95% genes showing < 1.2 fold change. Comparing the rapid autopsy to the failed heart identified 480 differentially expressed genes, including several types of collagens, lumican (LUM), natriuretic peptide A (NPPA) and connective tissue growth factor (CTGF), which allows for the clear separation between failing and non-failing heart based on gene expression profiles. CONCLUSIONS: Our results demonstrate that RNA from autopsy-derived tissue, even up to 24 hours of autolysis, can be used to identify biologically relevant expression pattern differences, thus serving as a practical source for gene expression experiments.

SUBMITTER: Gupta S

PROVIDER: S-EPMC3342086 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Postmortem cardiac tissue maintains gene expression profile even after late harvesting.

Gupta Simone S Halushka Marc K MK Hilton Gina M GM Arking Dan E DE

BMC genomics 20120117

<h4>Background</h4>Gene expression studies can be used to help identify disease-associated genes by comparing the levels of expressed transcripts between cases and controls, and to identify functional genetic variants (expression quantitative loci or eQTLs) by comparing expression levels between individuals with different genotypes. While many of these studies are performed in blood or lymphoblastoid cell lines due to tissue accessibility, the relevance of expression differences in tissues that ...[more]

PMID: 22251372

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Project description:Gene expression studies are used to help identify disease-associated genes, by comparing the levels of expressed transcripts between cases and controls, and to identify functional genetic variants known as expression quantitative loci (eQTLs). While many of these studies are performed in blood or lymphoblastoid cell lines due to tissue accessibility, the relevance of expression differences in tissues that are not the primary site of disease is unclear. Further, many eQTLs are tissue specific. Thus, there is a clear and compelling need to conduct gene expression studies in tissues that are specifically relevant to the disease of interest. One major technical concern about using autopsy-derived tissue is how representative it is of physiologic conditions, given the effect of postmortem interval on tissue degradation. In this study, we monitored the gene expression of 13 tissue samples harvested from a rapid autopsy heart (non-failed heart) and 7 from a cardiac explant (failed heart) through 24 hours of autolysis. The 24 hour autopsy simulation design reflects a typical autopsy scenario where a body may begin cooling to ambient temperature for ~12 hours, before transportation and storage in a refrigerated room in a morgue. In addition, we also simulated a scenario wherein the body was left at room temperature for up to 24 hours before being found. RNA from the 20 samples and triplicate from the HeLa cell line were run on the Affymetrix Exon arrays according to the manufacturer's protocol. The expression profiles of 7 cardiac tissue samples from the cardiac transplant operation (explant/failed heart) and 13 from a rapid-autopsy program (autopsy/non-failed heart) were harvested under the cold- and warm-24 hour autolysis conditions. The 7 explant samples include - 2 biological replicates at 0 hr, 1 at 6 hrs, 1 at 12 hrs, 2 biological replicates at 18 hr cold-autolysis condition and 1 at 18 hr warm-autolysis condition. The 13 autopsy samples include - 3 biological replicates at 0 hr (2 from the left and 1 from the right ventricle), 1 at 6 hrs, 2 biological replicates at 12 hrs (1 from the left and 1 from the right ventricle), 3 biological replicates at 18 hr cold-autolysis condition (2 from the left and 1 from the right ventricle), 2 biological replicates at 18 hr warm-autolysis condition ( 1 from the left and 1 from the right ventricle), 1 at 24 hr cold-autolysis condition and 1 at 24 hr warm-autolysis condition. Gene expression profiles of triplicate liver and heart exon array data obtained from Affymetrix were also used as reference .

Project description:Psychiatric stress has been associated with accelerated epigenetic aging (i.e., when estimates of cellular age based on DNA methylation exceed chronological age) in both blood and brain tissue. Little is known about the downstream biological effects of accelerated epigenetic age on gene expression. In this study we examined associations between DNA methylation-derived estimates of cellular age that range from decelerated to accelerated relative to chronological age ("DNAm age residuals") and transcriptome-wide gene expression. This was examined using tissue from three post-mortem cortical regions (ventromedial and dorsolateral prefrontal cortex and motor cortex, n = 97) from the VA National PTSD Brain Bank. In addition, we examined how posttraumatic stress disorder (PTSD) and alcohol-use disorders (AUD) moderated the association between DNAm age residuals and gene expression. Transcriptome-wide results across brain regions, psychiatric diagnoses, and cohorts (full sample and male and female subsets) revealed experiment-wide differential expression of 11 genes in association with PTSD or AUD in interaction with DNAm age residuals. This included the inflammation-related genes IL1B, RCOR2, and GCNT1. Candidate gene class analyses and gene network enrichment analyses further supported differential expression of inflammation/immune gene networks as well as glucocorticoid, circadian, and oxidative stress-related genes. Gene co-expression network modules suggested enrichment of myelination related processes and oligodendrocyte enrichment in association with DNAm age residuals in the presence of psychopathology. Collectively, results suggest that psychiatric stress accentuates the association between advanced epigenetic age and expression of inflammation genes in the brain. This highlights the role of inflammatory processes in the pathophysiology of accelerated cellular aging and suggests that inflammatory pathways may link accelerated cellular aging to premature disease onset and neurodegeneration, particularly in stressed populations. This suggests that anti-inflammatory interventions may be an important direction to pursue in evaluating ways to prevent or delay cellular aging and increase resilience to diseases of aging.

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Postmortem cardiac tissue maintains gene expression profile even after late harvesting.

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Postmortem cardiac tissue maintains gene expression profile even after late harvesting.

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