A systems-level study of the role of epigenetics in mediating in utero environmental influences on genome function and transgenerational effects

理解为什么个体在个人特征或疾病易感性方面是不同的，即“表型”，这仍然是生物学面临的最大挑战之一。到目前为止，大多数研究都集中在出生后的遗传变异或环境因素上。然而，最近的证据表明，宫内环境也可以影响成人的表型。此外，有人推测后代也会受到影响，即对某些表型和疾病的遗传易感性可能是父母或祖父母在宫内发育过程中受到环境影响的结果。但这些现象背后的分子机制是什么，也被称为发育编程？这些细胞必须保留对宫内环境的“记忆”，有几条证据表明，这种记忆存在于DNA的表观遗传修饰中。表观遗传修饰，如将甲基添加到DNA中，自然发生并控制基因的表达。最近的一些小规模研究表明，不利的宫内环境，如母亲在怀孕期间摄入不足的蛋白质，会在胎儿中诱导异常的表观遗传变化(表观突变)。这些表观突变在个体的一生中传播，因此成为宫内环境的记忆，并最终影响成人的表型结果。值得注意的是，表观突变不会改变DNA序列--只有表观遗传状态会改变。然而，关于表观遗传机制如何调节发育编程的影响的两个最重要的问题仍然没有得到回答：(I)这些表观突变发生在基因组的哪里；(Ii)这些表观突变中的哪些表观突变会遗传给后代？由于最近的技术进步，使我们能够同时研究基因组中的所有基因，我们现在可以进行强大的实验，可以解决这些非常重要的问题。在我的研究中，我将使用尖端的实验方法，结合使用模型生物和计算生物学，以了解暴露在低蛋白(LP)宫内环境中的影响。LP模型已被证明具有广泛的生理效应，最重要的是，它与出于经济或文化原因而消费低蛋白质饮食的人群有关。这个项目将揭示与发展规划相关的基本表观遗传机制的重要见解。

Understanding why individuals are different, in terms of their personal traits or predisposition to diseases i.e. 'phenotypes', remains one of biology's biggest challenges. To date, most studies have focused on either genetic variation or environmental factors that operate after birth. However, recent evidence suggests that the intrauterine environment can also influence adult phenotypes. Furthermore, it has been speculated that subsequent generations can also be affected, that is, the inherited predisposition to certain phenotypes and diseases can result from environmental influences during the intrauterine development of the parents or grandparents. But what are the molecular mechanisms that underlie these phenomena, also known as developmental programming? The cells must retain a 'memory' of the intrauterine environment and several lines of evidence suggest that the memory resides in epigenetic modifications of the DNA. Epigenetic modifications, such as addition of methyl groups to the DNA, occur naturally and control the expression of genes. A number of recent small-scale studies have shown that an adverse intrauterine environment, such as the mother consuming inadequate protein during pregnancy, induces aberrant epigenetic changes (epimutations) in the foetus. These epimutations are propagated throughout the life of the individual, hence becoming the memory of the intrauterine environment, and eventually influencing phenotypic outcomes in the adult. It is important to note that epimutations do not change the DNA sequence - only the epigenetic state is changed. However, two of the most important questions about how epigenetic mechanisms mediate the effects of developmental programming remain unanswered: (i) Where in the genome do these epimutations occur (ii) Which of these epimutations are passed on to future generations? As a result of recent technological advances, that allow us to simultaneously study the all genes in a genome, we can now perform powerful experiments that can address these very important issues. For my study, I will be using cutting-edge experimental approaches that combine the use of model organisms and computational biology, to understand the effects of exposure to a low-protein (LP) intrauterine environment. The LP model has been shown to have wide-ranging physiological effects, and most importantly, it is relevant to human populations who consume low protein diets for economic or cultural reasons. This project will reveal important insights into the fundamental epigenetic mechanisms associated with developmental programming.