DNA Methylation Developmental Programming and Cellular Memory: The Molecular Consequences of Folate Depletion In Utero

母亲营养不良会对后代的长期健康和福祉产生深远影响，并可能导致过早衰老。这些对健康的不利影响包括常见疾病，如肥胖、2型糖尿病和心血管疾病。当后代体重增加的速度比预期的要快时，这些疾病的风险似乎会加剧。在初步研究中，我们观察到，在怀孕和哺乳期间给予低叶酸（一种B族维生素）饮食的母亲所生的小鼠比叶酸供应正常的母亲所生的小鼠成年后体重更重，尽管事实上两组小鼠在断奶时的体重没有差异，并且所有小鼠在断奶时接受相同的饮食。这表明母体营养损伤被小鼠组织“记住”，并表现为更快速的生长。表观遗传标记的变化被认为是负责细胞对早期生活经历的“记忆”的最重要机制之一。表观遗传学描述了基因组的化学变化，这些变化调节基因表达（打开）的时间和位置，但不改变主要的DNA序列。对表观遗传标记的最好理解是DNA甲基化，即向DNA添加CH3（甲基）基团。在我们的小鼠研究中，我们发现叶酸缺乏的母亲所生的成年小鼠的DNA中CH3基团较少。在后续研究中，我们发现母体叶酸缺乏导致胎儿肝脏中超过600个基因的表达改变。在本项目中，我们将更详细地研究母体叶酸供应量低对后代生长和体脂的影响，并研究断奶后饲喂高脂肪和低脂饮食的影响。我们预计，高脂肪饮食（基于西方人类饮食的组成）将加剧产妇营养损害的影响。我们将使用最先进的磁共振成像技术来测量活老鼠体内有多少脂肪，以及脂肪储存在身体的哪些部位。在人类中，储存在腹部的脂肪与几种常见疾病的高风险有关，包括2型糖尿病，心血管疾病和肠癌。然后，我们将探讨这些表型变化的机制。我们将专注于识别基因的表达已被改变，通过改变表观遗传标记，并试图阐明导致基因被关闭或打开，不适当的分子事件。

Summary Poor maternal nutrition can have profound effects on the long-term health and wellbeing of offspring and may cause premature ageing. These adverse effects on health include common diseases such as obesity, type 2 diabetes and cardiovascular disease. The risk of these conditions appears to be exacerbated when the offspring gain weight more quickly than would have been expected. In preliminary studies, we observed that mice born to mothers given diets low in folate (a B vitamin) during pregnancy and lactation became heavier adults than those born to mothers with normal folate supply despite the fact that there were no differences in body weight between the two groups of mice at weaning and that all mice received the same diet from weaning. This suggests that the maternal nutritional insult was 'remembered' by the mouse tissues and expressed as more rapid growth. Change in epigenetic markings is one of the most important mechanisms believed to be responsible for cellular 'memorisation' of early life experiences. Epigenetics describes chemical changes to the genome which regulate when and where genes are expressed (turned on) but which do not alter the primary DNA sequence. The best understood of the epigenetic marks is DNA methylation i.e. the addition of CH3 (methyl) groups to DNA. In our mouse studies we found that there were fewer CH3 groups in the DNA from adult mice born to the folate-depleted mothers. In follow up studies we have found that maternal folate depletion resulted in altered expression of over 600 genes in fetal liver. In this project we will investigate in more detail the effects of low maternal folate supply on growth and body fatness of the offspring and we will examine the effects of feeding high v. low fat diets from weaning. We anticipate that the high fat diet (based on the composition of Western human diets) will exacerbate the effects of the maternal nutritional insult. We will use state-of-the-art magnetic resonance imaging to allow us to measure how much fat is in the live mice and in which parts of the body it is stored. In humans, fat stored in the abdomen is associated with higher risk of several common disease including type 2 diabetes, cardiovascular disease and bowel cancer. We will then explore the mechanisms responsible for these phenotypic changes. We will focus on identification of genes whose expression has been changed through altered epigenetic markings and attempt to elucidate the molecular events leading to the genes being switched off, or switched on, inappropriately.