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

遗传学和表观遗传学如何相互作用来影响上下文依赖性增强子的活性？

• 批准号: BB/W017598/1
• 负责人: Alasdair MacKenzie
• 金额: $ 74.69万
• 依托单位: University of Aberdeen
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW017598%2F1
• 关键词: How; do; genetics; epigenetics; interact

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

过量摄入酒精和焦虑等行为对人们一生的健康都有重大影响。因此，了解控制酒精摄入量和焦虑的遗传和环境过程，将为开发未来的预防性干预和治疗提供机会。上下文依赖的增强子充当基因开关，负责在特定的身体细胞和特定的时间开启和关闭特定的基因。这些增强剂对健康的重要性，以及它们在疾病中的可能作用，已经被大量的遗传学研究所强调，这些研究表明，95%的复杂疾病可以归因于调控序列(如增强剂)中的DNA变化，这些疾病对我们以健康的方式衰老的能力产生负面影响。关键的是，我们之前发现，环境因素，包括饮食脂肪摄入量，也可以通过影响增强子序列的活性来影响下一代的健康跨度。不幸的是，我们对这些基因开关的生物学知之甚少，它们如何在不同的物种中受到遗传和性别的影响，或者饮食如何改变它们的活动，以及它们对酒精摄取和焦虑的影响。我们假设，控制神经肽(在大脑中产生并已知会影响行为的短蛋白)基因的上下文相关增强子在遗传、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，如酒精摄取和焦虑。为了解决这一假设，我们确定了一种增强子(GAL5.1)，该增强子在老鼠和人类中几乎没有变化。GAL5.1在大脑的特定细胞中启动一种名为GAL的神经肽基因，GAL控制酒精摄取和焦虑。重要的是，我们发现这种增强子包含与人类男性焦虑和酗酒有关的DNA序列变化(多态)。此外，我们从小鼠身上删除了这种增强子，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的焦虑。这是第一次在老鼠和人类身上发现了高度依赖于环境的增强剂，它可以控制乙醇的摄入和焦虑，这些行为在整个生命过程中对健康有很大影响。这种增强子的识别为我们的国际公认的多学科团队(阿伯丁；麦克尤恩，麦肯齐，曼彻斯特；穆尔特罗伊德)提供了一个独特的机会来识别i)调控对人类健康有严重影响的行为(乙醇摄取和焦虑)的上下文相关增强子的分子机制，ii)饮食如何与DNA序列变化(多态性)和性别相互作用来影响上下文相关增强子的活性，并比较不同物种(老鼠/人)的影响。GAL5.1的鉴定及其作为上下文依赖增强子的特征，为确定影响增强子活性的分子、遗传和饮食依赖机制提供了一个无与伦比的机会，该增强子的活性可能直接影响乙醇摄入和焦虑以及我们健康衰老的能力