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- Title
Blood and brain gene expression signatures of chronic intermittent ethanol consumption in mice.
- Authors
Ferguson, Laura B.; Roberts, Amanda J.; Mayfield, R. Dayne; Messing, Robert O.
- Abstract
Alcohol Use Disorder (AUD) is a chronic, relapsing syndrome diagnosed by a heterogeneous set of behavioral signs and symptoms. There are no laboratory tests that provide direct objective evidence for diagnosis. Microarray and RNA-Seq technologies enable genome-wide transcriptome profiling at low costs and provide an opportunity to identify biomarkers to facilitate diagnosis, prognosis, and treatment of patients. However, access to brain tissue in living patients is not possible. Blood contains cellular and extracellular RNAs that provide disease-relevant information for some brain diseases. We hypothesized that blood gene expression profiles can be used to diagnose AUD. We profiled brain (prefrontal cortex, amygdala, and hypothalamus) and blood gene expression levels in C57BL/6J mice using RNA-seq one week after chronic intermittent ethanol (CIE) exposure, a mouse model of alcohol dependence. We found a high degree of preservation (rho range: [0.50, 0.67]) between blood and brain transcript levels. There was small overlap between blood and brain DEGs, and considerable overlap of gene networks perturbed after CIE related to cell-cell signaling (e.g., GABA and glutamate receptor signaling), immune responses (e.g., antigen presentation), and protein processing / mitochondrial functioning (e.g., ubiquitination, oxidative phosphorylation). Blood gene expression data were used to train classifiers (logistic regression, random forest, and partial least squares discriminant analysis), which were highly accurate at predicting alcohol dependence status (maximum AUC: 90.1%). These results suggest that gene expression profiles from peripheral blood samples contain a biological signature of alcohol dependence that can discriminate between CIE and Air subjects. Author summary: Recent evidence in mice suggests that brain gene expression profiles can predict disease status as well as predict drugs effective for treating alcoholism. However, it is not possible to obtain brain specimens from human patients which limits the usefulness of this approach. This study investigated the extent to which blood can act as a surrogate for brain tissue and predict CIE-induced alcohol dependence status. This information lays critical groundwork for developing molecular-based diagnosis and treatment options for alcoholic patients and provides insights into the biological mechanisms that might contribute to the transition from recreational alcohol use to excessive drinking.
- Subjects
INTERNATIONAL Commission on Illumination; GENE expression; ALCOHOL; GENE expression profiling; HYPOTHALAMUS; ALCOHOLISM; GENE regulatory networks; BRAIN diseases
- Publication
PLoS Computational Biology, 2022, Vol 18, Issue 2, p1
- ISSN
1553-734X
- Publication type
Article
- DOI
10.1371/journal.pcbi.1009800