An ancient polymorphic regulatory region within the BDNF gene associated with obesity modulates anxiety-like behaviour in mice and humans
An ancient polymorphic regulatory region within the BDNF gene associated with obesity modulates anxiety-like behaviour in mice and humans
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BDNF 基因内与肥胖相关的古老多态性调节区域可调节小鼠和人类的焦虑样行为
DOI：
10.1101/2021.07.20.452916
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
McEwan A
中科院分区：
文献类型：
--
作者：
McEwan A
在最近的COVID-19大流行期间，肥胖和焦虑是值得注意的疾病，对社会的影响越来越大。了解控制这些疾病易感性的机制将提高我们的生活质量和对未来流行病的抵御能力。在目前的研究中，我们探索了BDNF基因中一个高度保守的调控区域（BE5.1）的功能，该区域具有与肥胖密切相关的多态性（rs10767664;p= 4.69 × 10-26）。原代细胞分析表明，BE5.1的主要t等位基因是一个增强子，而肥胖相关的a等位基因则不是。然而，CRISPR/CAS9从小鼠基因组中删除BE5.1 （BE5.1 ko）对下丘脑中BDNF转录本的表达没有显著影响，28天后体重增加没有变化，只略微显著增加了食物摄入量。然而，雌性小鼠杏仁核的转录本显著增加，零迷宫和大理石掩埋测试的升高表明，焦虑样行为显著增加，而地西泮可以逆转这种行为。与这些观察结果一致，人类GWAS队列分析显示rs10767664与人群焦虑之间存在显著关联。有趣的是，对人类GTEx eQTL数据库的查询显示，与rs10767664相关的BDNF mRNA水平没有影响，但对BDNF-反义（BDNF- as）基因的表达和剪接有非常显著的影响。随后观察到，BE5.1的缺失也显著降低了小鼠BDNF- as的表达，这表明小鼠和人类共同调节BDNF表达的新机制，有助于调节两种物种的情绪和焦虑。
Obesity and anxiety are morbidities notable for their increased impact on society during the recent COVID-19 pandemic. Understanding the mechanisms governing susceptibility to these conditions will increase our quality of life and resilience to future pandemics. In the current study, we explored the function of a highly conserved regulatory region (BE5.1) within the BDNF gene that harbours a polymorphism strongly associated with obesity (rs10767664;p= 4.69 × 10–26). Analysis in primary cells suggested that the major T-allele of BE5.1 was an enhancer, whereas the obesity-associated A-allele was not. However, CRISPR/CAS9 deletion of BE5.1 from the mouse genome (BE5.1KO) produced no significant effect on the expression of BDNF transcripts in the hypothalamus, no change in weight gain after 28 days and only a marginally significant increase in food intake. Nevertheless, transcripts were significantly increased in the amygdala of female mice and elevated zero maze and marble-burying tests demonstrated a significant increase in anxiety-like behaviour that could be reversed by diazepam. Consistent with these observations, human GWAS cohort analysis demonstrated a significant association between rs10767664 and anxiousness in human populations. Intriguingly, interrogation of the human GTEx eQTL database demonstrated no effect on BDNF mRNA levels associated with rs10767664 but a highly significant effect on BDNF-antisense (BDNF-AS) gene expression and splicing. The subsequent observation that deletion of BE5.1 also significantly reduced BDNF-AS expression in mice suggests a novel mechanism in the regulation of BDNF expression common to mice and humans, which contributes to the modulation of mood and anxiety in both species.
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影响因子：
9.3
作者：
Shanley L;Lear M;Davidson S;Ross R;MacKenzie A
通讯作者：
MacKenzie A
影响因子：
10.6
作者：
Hing, Benjamin;Davidson, Scott;Lear, Marrisa;Breen, Gerome;Quinn, John;McGuffin, Peter;MacKenzie, Alasdair
通讯作者：
MacKenzie, Alasdair
影响因子：
8.8
作者：
Lettice LA;Devenney P;De Angelis C;Hill RE
通讯作者：
Hill RE
由杏仁核特异性 ECR1 增强子驱动的 LacZ 标记基因与 P 物质神经肽的细胞共表达
影响因子：
11
作者：
S. Davidson;K. Miller;A. Dowell;A. Gildea;A. MacKenzie
通讯作者：
A. MacKenzie
教员意见建议保守的 ECR1 增强子内的疾病相关多态性差异调节大麻素 1 受体基因启动子的组织特异性活性；
影响因子：
2.9
作者：
W. Wasserman
通讯作者：
W. Wasserman