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Genetic and epigenetic influences modulating the tissue specific regulation of the cannabinoid receptor -1 gene (CB1); implications for cannabinoid pharmacogenetics

Elizabeth A. Hay, Philip Cowie, Andrew McEwan, Dana Wilson, Ruth Ross, Perry Barrett, Roger G. Pertwee, Alasdair MacKenzie
doi: https://doi.org/10.1101/544585
Elizabeth A. Hay
1School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, UK
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Philip Cowie
1School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, UK
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Andrew McEwan
1School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, UK
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Dana Wilson
2Rowett Institute of Nutrition and Health, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, UK
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Ruth Ross
3Department of Pharmacology and Toxicology, Room 4207, Medical Sciences Building, 1 King’s College Circle, Toronto, Ontario, M5S 1A8 Canada
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Perry Barrett
2Rowett Institute of Nutrition and Health, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, UK
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Roger G. Pertwee
1School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, UK
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Alasdair MacKenzie
1School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, UK
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  • For correspondence: mbi167@abdn.ac.uk
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Abstract

Cannabinoid receptor-1 (CB1) represents a potential drug target against conditions that include obesity and substance abuse. However, drug trials targeting CB1 (encoded by the CNR1 gene) have been compromised by differences in patient response. Towards addressing the hypothesis that genetic and epigenetic changes within the regulatory regions controlling CNR1 expression contribute to these differences, we isolated the human CNR1 promotor (CNR1prom) and demonstrate its activity in primary cells and transgenic mice. We also provide evidence of CNR1prom in CB1 autoregulation and its repression by DNA-methylation. We further characterised a conserved regulatory sequence (ECR1) in CNR1 intron 2 that contained a polymorphism in linkage disequilibrium with disease associated SNPs. Deletion of ECR1 from mice using CRISPR genome editing significantly reduced CNR1 expression in the hippocampus. These mice also displayed reduced ethanol intake and hypothermia response to CB1 agonism. Moreover, human specific C-allele variants of ECR1 (ECR1(C)) drove higher levels of CNR1prom activity in hippocampal cells than did the ancestral T-allele. We further demonstrate a role for the AP-1 transcription factor in driving higher ECR1(C) activity. In the context of the known roles of CB1 the current study suggests a mechanism through which ECR1(C) may be neuroprotective in the hippocampus against stress. The cell-specific approaches used in our study to determine the functional effects of genetic and epigenetic changes on the activity of tissue-specific regulatory elements at the CNR1 locus represent an important step in gaining a mechanistic understanding of cannabinoid pharmacogenetics.

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Posted March 05, 2019.
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Genetic and epigenetic influences modulating the tissue specific regulation of the cannabinoid receptor -1 gene (CB1); implications for cannabinoid pharmacogenetics
Elizabeth A. Hay, Philip Cowie, Andrew McEwan, Dana Wilson, Ruth Ross, Perry Barrett, Roger G. Pertwee, Alasdair MacKenzie
bioRxiv 544585; doi: https://doi.org/10.1101/544585
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Genetic and epigenetic influences modulating the tissue specific regulation of the cannabinoid receptor -1 gene (CB1); implications for cannabinoid pharmacogenetics
Elizabeth A. Hay, Philip Cowie, Andrew McEwan, Dana Wilson, Ruth Ross, Perry Barrett, Roger G. Pertwee, Alasdair MacKenzie
bioRxiv 544585; doi: https://doi.org/10.1101/544585

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