Allele-specific differences in activity of a novel cannabinoid receptor 1 (CNR1) gene intronic enhancer in hypothalamus, dorsal root ganglia, and hippocampus.
Allele-specific differences in activity of a novel cannabinoid receptor 1 (CNR1) gene intronic enhancer in hypothalamus, dorsal root ganglia, and hippocampus.
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DOI：
10.1074/jbc.m111.336750
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发表时间：
2012-04-13
期刊：
影响因子：
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通讯作者：
MacKenzie A
中科院分区：
文献类型：
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作者：
Nicoll G;Davidson S;Shanley L;Hing B;Lear M;McGuffin P;Ross R;MacKenzie A
背景：CNR 1基因内含子2含有多个与疾病相关的SNPs。结果：CNR 1内含子2的一个新的增强子的等位基因变体影响其在下丘脑和海马的MAPK反应。结论：增强子基因可能与肥胖和成瘾行为存在功能关联。意义：了解CNR 1多态性对基因调控的影响将加速对人类疾病的理解。编码大麻素受体1（CB 1）的CNR 1基因内含子2内的多态性与成瘾、肥胖和脑容量不足有关。我们使用比较基因组学来鉴定CNR 1基因内含子2中的多态性（rs 9444584-C/T）序列（ECR 1），该序列已保守了3.1亿年。ECR 1的C等位基因（ECR 1（C））在下丘脑和背根神经节细胞中作为增强子，并通过MEKK通路对MAPK激活产生应答，但在海马细胞中不起作用。然而，ECR 1（T）在下丘脑和背根神经节细胞中的活性显著更高，但与ECR 1（C）相反，ECR 1（T）在海马细胞中的活性显著更高，在海马细胞中，ECR 1（T）也对MAPK的激活有强烈反应。有趣的是，rs 9444584与另外两个SNP（rs 9450898（r2 = 0.841）和rs 2023239（r2 = 0.920））处于强连锁不平衡，这两个SNP与成瘾、肥胖（rs 2023239）和精神分裂症患者中由于大麻滥用导致的额颞白色物质体积减少（rs 9450898）相关。考虑到它们的高度连锁不平衡和与ECR 1（C）相比，ECR 1（T）对MAPK信号传导的反应增加，rs 9444584的不同等位基因的功能效应可能在与rs 9450898和rs 2023239相关的病症中发挥作用。对ECR 1不同等位基因的进一步分析可能会导致对CNR 1基因失调在这些疾病以及慢性炎症性疼痛中的作用有更深入的了解。
Background: Intron 2 of CNR1 gene contains multiple disease-associated SNPs. Results: Allelic variants of a novel enhancer in CNR1 intron 2 affect its MAPK response in hypothalamus and hippocampus. Conclusion: Alleles of enhancer may be functionally linked to obesity and addictive behavior. Significance: Understanding the effects of CNR1 polymorphisms on gene regulation will accelerate understanding of human disease. Polymorphisms within intron 2 of the CNR1 gene, which encodes cannabinoid receptor 1 (CB1), have been associated with addiction, obesity, and brain volume deficits. We used comparative genomics to identify a polymorphic (rs9444584-C/T) sequence (ECR1) in intron 2 of the CNR1 gene that had been conserved for 310 million years. The C-allele of ECR1 (ECR1(C)) acted as an enhancer in hypothalamic and dorsal root ganglia cells and responded to MAPK activation through the MEKK pathway but not in hippocampal cells. However, ECR1(T) was significantly more active in hypothalamic and dorsal root ganglia cells but, significantly, and in contrast to ECR1(C), was highly active in hippocampal cells where it also responded strongly to activation of MAPK. Intriguingly, rs9444584 is in strong linkage disequilibrium with two other SNPs (rs9450898 (r2 = 0.841) and rs2023239 (r2 = 0.920)) that have been associated with addiction, obesity (rs2023239), and reduced fronto-temporal white matter volumes in schizophrenia patients as a result of cannabis misuse (rs9450898). Considering their high linkage disequilibrium and the increased response of ECR1(T) to MAPK signaling when compared with ECR1(C), it is possible that the functional effects of the different alleles of rs9444584 may play a role in the conditions associated with rs9450898 and rs2023239. Further analysis of the different alleles of ECR1 may lead to a greater understanding of the role of CNR1 gene misregulation in these conditions as well as chronic inflammatory pain.