Chronic Alcohol Exposure and the Circadian Clock Mutation Exert Tissue-Specific Effects on Gene Expression in Mouse Hippocampus, Liver, and Proximal Colon.
BACKGROUND
Chronic alcohol exposure exerts numerous adverse effects, although the specific mechanisms underlying these negative effects on different tissues are not completely understood. Alcohol also affects core properties of the circadian clock system, and it has been shown that disruption of circadian rhythms confers vulnerability to alcohol-induced pathology of the gastrointestinal barrier and liver. Despite these findings, little is known of the molecular interactions between alcohol and the circadian clock system, especially regarding implications for tissue-specific susceptibility to alcohol pathologies. The aim of this study was to identify changes in expression of genes relevant to alcohol pathologies and circadian clock function in different tissues in response to chronic alcohol intake.


METHODS
Wild-type and circadian Clock(Δ19) mutant mice were subjected to a 10-week chronic alcohol protocol, after which hippocampal, liver, and proximal colon tissues were harvested for gene expression analysis using a custom-designed multiplex magnetic bead hybridization assay that provided quantitative assessment of 80 mRNA targets of interest, including 5 housekeeping genes and a predetermined set of 75 genes relevant for alcohol pathology and circadian clock function.


RESULTS
Significant alterations in expression levels attributable to genotype, alcohol, and/or a genotype by alcohol interaction were observed in all 3 tissues, with distinct patterns of expression changes observed in each. Of particular interest was the finding that a high proportion of genes involved in inflammation and metabolism on the array was significantly affected by alcohol and the Clock(Δ19) mutation in the hippocampus, suggesting a suite of molecular changes that may contribute to pathological change.


CONCLUSIONS
These results reveal the tissue-specific nature of gene expression responses to chronic alcohol exposure and the Clock(Δ19) mutation and identify specific expression profiles that may contribute to tissue-specific vulnerability to alcohol-induced injury in the brain, colon, and liver.
Center for Sleep & Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, Illinois.
Keith C
KC
Summa
Center for Sleep & Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, Illinois.
Peng
P
Jiang
Center for Sleep & Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, Illinois.
Karrie
K
Fitzpatrick
Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois.
Robin M
RM
Voigt
Center for Sleep & Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, Illinois.
Samuel J
SJ
Bowers
Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois.|Department of Biochemistry, Rush University Medical Center, Chicago, Illinois.
Christopher B
CB
Forsyth
Center for Sleep & Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, Illinois.
Martha H
MH
Vitaterna
Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois.|Department of Biochemistry, Rush University Medical Center, Chicago, Illinois.|Department of Pharmacology, Rush University Medical Center, Chicago, Illinois.|Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois.|Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Science, Utrecht University, Utrecht, the Netherlands.
Ali
A
Keshavarzian
Center for Sleep & Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, Illinois.
Fred W
FW
Turek
D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics*; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D009154:Mutation; D009928:Organ Specificity / Q000187:drug effects
D000431:Ethanol; D056926:CLOCK Proteins; C538944:Clock protein, mouse
Alcohol; Circadian Rhythms; Clock Mutation; Gene Expression; Mouse Models