title: A novel heat shock protein alpha 8 (Hspa8) molecular network mediating responses to stress- and ethanol-related behaviors.
abstract: Genetic differences mediate individual differences in susceptibility and responses to stress and ethanol, although, the specific molecular pathways that control these responses are not fully understood. Heat shock protein alpha 8 (Hspa8) is a molecular chaperone and member of the heat shock protein family that plays an integral role in the stress response and that has been implicated as an ethanol-responsive gene. Therefore, we assessed its role in mediating responses to stress and ethanol across varying genetic backgrounds. The hippocampus is an important mediator of these responses, and thus, was examined in the BXD family of mice in this study. We conducted bioinformatic analyses to dissect genetic factors modulating Hspa8 expression, identify downstream targets of Hspa8, and examined its role. Hspa8 is trans-regulated by a gene or genes on chromosome 14 and is part of a molecular network that regulates stress- and ethanol-related behaviors. To determine additional components of this network, we identified direct or indirect targets of Hspa8 and show that these genes, as predicted, participate in processes such as protein folding and organic substance metabolic processes. Two phenotypes that map to the Hspa8 locus are anxiety-related and numerous other anxiety- and/or ethanol-related behaviors significantly correlate with Hspa8 expression. To more directly assay this relationship, we examined differences in gene expression following exposure to stress or alcohol and showed treatment-related differential expression of Hspa8 and a subset of the members of its network. Our findings suggest that Hspa8 plays a vital role in genetic differences in responses to stress and ethanol and their interactions.
authors.affiliation: Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Urquhart
authors.affiliation: Department of Neurology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Baker
authors.affiliation: The International Hospital of Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Yan
authors.affiliation: Department of Psychology, University of Memphis, Memphis, TN, 38152, USA.
authors.forename: Melloni N
authors.initials: MN
authors.lastname: Cook
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
authors.forename: Byron C
authors.initials: BC
authors.lastname: Jones
authors.affiliation: Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA. khamre@uthsc.edu.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Hamre
authors.affiliation: Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA. lulu521uthsc@gmail.com.|Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, 38163, USA. lulu521uthsc@gmail.com.|Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College of Nantong University, Nantong, China. lulu521uthsc@gmail.com.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics / Q000523:psychology*; D000818:Animals; D001522:Behavior, Animal; D033481:Chromosomes, Mammalian / Q000235:genetics; D005260:Female; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D050883:HSC70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D013045:Species Specificity; D013315:Stress, Psychological / Q000235:genetics / Q000523:psychology*
chemical_list: D050883:HSC70 Heat-Shock Proteins; C494372:Hspa8 protein, mouse
keywords: Alcohol; Anxiety; BXD mice; QTL; Quantitative trait locus