Epigenetic regulation of gene expression as a mechanism of nutritional programming and developmental origins of health and disease

一个人的饮食在生命的任何阶段都有重要的健康问题——毕竟“我们吃什么就是什么”。然而，有证据表明，孕妇的饮食尤其重要，因为它对后代的健康有着重大的长期影响——所以，在某种程度上，“我们的母亲在怀孕期间吃什么，我们就吃什么”。怀孕期间营养不良的母亲所生的正常足月婴儿通常体重较低。研究表明，出生体重过轻的人不仅在分娩时存活的可能性较低，而且在成年后患糖尿病、高血压和心脏病等各种常见疾病的风险也大大增加。早期发育不良与成年后疾病之间关系的根本原因尚不清楚，但我们认为，妇女在怀孕期间的饮食质量至关重要。我们破译人类疾病机制的许多尝试都依赖并受益于对动物模型的研究。我们在一个啮齿类动物模型中表明，如果怀孕的动物在怀孕期间摄入的蛋白质太少，它们的婴儿出生时就会很小，成年后会患上糖尿病。我们已经确定了胰腺中重要的基因，与对照动物相比，这些基因在蛋白质限制母亲的后代中表达水平较低。我们现在计划进一步研究这些动物，以了解限制饮食如何能够干扰参与糖尿病发病机制的关键基因的表达。我们特别感兴趣的是研究表观遗传机制，即能够改变基因活性而不改变其DNA序列的机制，这可能是由怀孕期间营养变化引发的。我们还想更准确地知道，在怀孕期间，母亲的饮食质量对生下健康的婴儿最重要。这将使我们能够识别有风险的个体，并制定干预策略，以改善孕妇及其后代的健康。

The diet of an individual has important health issues at any stage of life - 'we are what we eat' after all. However, there is evidence to suggest that the diet of a pregnant woman is particularly important as it has major long-term implications on the health of her offspring - so, in some ways 'we also are what our mothers ate during pregnancy'. Normal term babies born from mothers with poor nutrition during pregnancy usually have a low weight. It has been shown that individuals with a low birth weight are not only less likely to survive delivery but are also at substantially increased risk of developing various common diseases such as diabetes, hypertension and heart disease in adulthood. The underlying causes of the relationship between poor early growth and disease in adulthood are not known, but we believe that the quality of the diet of women during pregnancy is critically important. Many of our attempts to decipher mechanisms of human diseases both rely and benefit from studying animal models. We have shown in a rodent model that if pregnant animals have too little protein during pregnancy their babies are small at birth and develop diabetes in adulthood. We have identified important genes in the pancreas that are expressed at low levels in the offspring of protein-restricted mothers compared to control animals. We now plan further to study these animals to understand how a restricted diet is able to perturb expression of key genes involved in pathogenesis of diabetes. We are particularly interested in studying epigenetic mechanisms - that is mechanisms able to change activity of a gene without altering its DNA sequence - that could be triggered by nutritional changes during pregnancy. We also want to know more precisely at which time/s during pregnancy the quality of the mother's diet is most important for giving birth to healthy babies. This will enable us to both identify at risk individuals and to develop intervention strategies to improve the health of both the pregnant women and their offspring.