How do genetics and epigenetics interact to influence the activity of a context-dependent enhancer?

诸如过量乙醇摄入和焦虑等行为对人的一生健康有重大影响。因此，了解几代人控制乙醇摄入和焦虑的遗传和环境过程，将为开发未来的预防干预和治疗提供机会。背景依赖性增强子充当基因开关，负责在特定时间和特定细胞中打开和关闭特定基因。这些增强子对健康的重要性以及它们在疾病中可能的作用已经被许多遗传研究（GWAS）所强调，这些研究表明，>95%的复杂疾病，这些疾病对我们以健康的方式衰老的能力产生负面影响，可以归因于调节序列（如增强子）内的DNA变化。重要的是，我们以前发现，环境因素，包括膳食脂肪摄入量，也可以通过影响增强子序列的活性来影响下一代的健康寿命。不幸的是，我们对这些基因开关的生物学知之甚少，它们如何受到不同物种的遗传和性别的影响，饮食如何改变它们的活性，以及它们对乙醇摄入和焦虑的影响，我们假设控制神经肽编码基因的环境依赖性增强子（大脑中产生的短蛋白质，已知会影响行为）在遗传、性别和饮食的相互作用中发挥作用，影响对健康寿命产生负面影响的行为，如酒精摄入和焦虑。为了解决这一假设，我们确定了一个增强子（GAL 5.1），在小鼠和人类中几乎保持不变。GAL 5.1在大脑的特定细胞中开启一种称为GAL的神经肽基因，GAL控制乙醇摄入和焦虑。重要的是，我们发现这种增强子含有与人类男性焦虑和酒精滥用相关的DNA序列变化（多态性）。此外，我们从小鼠中删除了这种增强子，发现不仅GAL基因（在小鼠中称为Gal）几乎关闭，而且这些小鼠没有喝那么多乙醇，雄性也没有遭受那么多焦虑。这是第一次在小鼠和人类中发现一种高度依赖于环境的增强子，它控制乙醇摄入和焦虑;在整个生命过程中对健康有强烈影响的行为。这种增强剂的鉴定为我们的国际公认的多学科团队提供了（阿伯丁;麦克尤恩，麦肯齐，曼彻斯特; Murgatroyd），这是一个独特的机会来确定i）调节行为的上下文依赖性增强子的分子机制（乙醇摄入量和焦虑）对人体健康有严重影响，2.饮食如何与DNA序列变化相互作用（多态性）和性别来影响上下文依赖性增强子的活性，并比较不同物种中的效果。iii）背景依赖性增强剂如何受到子宫中母体饮食的影响以影响后代的行为。GAL5.1的鉴定及其作为环境依赖性增强子的特征提供了确定影响增强子活性的分子、遗传和饮食依赖性机制的无与伦比的机会，所述增强子的活性可能对乙醇摄入和焦虑以及我们健康衰老的能力具有直接影响

Behaviours such as excess ethanol intake and anxiety have a major impact on people's health across the life-course. Thus, understanding the genetic and environmental processes that control ethanol intake and anxiety, across the generations, will provide opportunities to develop future preventative interventions and treatments. Context-dependant enhancers act as gene switches and are responsible for turning specific genes on and off in specific cells of the body and at specific times. The importance of these enhancers to health, and their possible role in disease, has been highlighted by numerous genetic studies (GWAS) which demonstrate that >95% of complex diseases, that negatively affect our ability to age in a healthy manner, can be attributed to DNA changes within regulatory sequences such as enhancers. Critically, we previously discovered that environmental factors, that can include dietary fat intake, can also impact the health span of the next generation by affecting the activity of enhancer sequences. Unfortunately, we know very little about the biology of these gene switches, how they are affected by genetics and sex in different species or how diet alters their activity, and their effects of ethanol intake and anxiety, through the generations.We hypothesised that context-dependant enhancers which control genes encoding neuropeptides (short proteins produced in the brain and known to influence behavior) play a role in the interaction of genetics, sex and diet to influence behaviours that negatively impact the health-span such as ethanol intake and anxiety. To address this hypothesis, we identified an enhancer (GAL5.1) that has remained almost unchanged in both mice and humans. GAL5.1 turns on a neuropeptide gene called GAL in specific cells of the brain where GAL controls ethanol intake and anxiety. Importantly we found that this enhancer contained DNA sequence changes (polymorphisms) that had been associated with anxiety and alcohol abuse in human males. Moreover, we deleted this enhancer from mice and found that, not only was the GAL gene (called Gal in mice) nearly turned off, but that these mice didn't drink as much ethanol and males did not suffer as much anxiety. This is the first time that a highly context-dependent enhancer has been identified in both mice and humans that controls ethanol intake and anxiety; behaviours with a strong impact on health through the life course. Identification of this enhancer provides our internationally recognised multidiscipline team (Aberdeen; McEwan, MacKenzie, Manchester; Murgatroyd) with a unique opportunity to identify i) The molecular mechanisms regulating a context-dependent enhancer which regulates behaviours (ethanol intake and anxiety) with a serious impact on human health, ii) How diet interacts with DNA sequence changes (polymorphisms) and sex to affect the activity of a context-dependant enhancer and compare the effects in different species(Mouse/human).iii) How a context-dependant enhancer is affected by maternal diet in the womb to impact the behaviour of subsequent generations. Identification of GAL5.1, and its characterisation as a context-dependent enhancer, provides an unparalleled opportunity to determine the molecular, genetic and dietary dependent mechanisms influencing the activity of an enhancer whose activity may have a direct impact on ethanol intake and anxiety and our ability to age healthily