The functional requirement for epigenetic systems in development and disease

接触烟草烟雾、化学品、空气污染物和营养等环境因素可对人体健康产生不利影响。这可能会导致通常存在于我们DNA上的“化学标签”发生变化。这些标签对应于“表观遗传标记”（DNA顶部），可以作为DNA功能的“条形码”，通过指示基因处于激活或沉默的条形码状态。条形码的变化可以代表环境诱导的基因表达变化，这些变化对细胞和组织的工作方式有下游的不利影响。这可能导致疾病易感性增强，例如导致癌症发病率增加，或与过早衰老过程有关。本课题将研究表观遗传标记在调控基因表达中的作用。胚胎干细胞（ESCs）是早期小鼠发育的模型，可以在培养皿中在不同的培养条件下生长，既可以促进它们的持续再生，也可以诱导它们分化成特定的组织类型，如神经组织。令人感兴趣的是，其中一个化学标签，5-甲基胞嘧啶（5mC），经历了指示分化状态和基因表达谱的程序性变化。我们将研究在DNA甲基化重编程中重要的关键酶（DNA甲基转移酶（Dnmts））的缺乏如何影响ESC分化。使用适当的模型系统，我们将进行详细的分析，以确定缺乏Dnmt酶如何改变细胞正常分化的能力。我们使用高分辨率分子分析和成像技术来更好地了解表观遗传学对发育和隐含疾病状态的贡献。这些研究为强有力的疾病诊断测试的新发展提供了基础，为监测环境暴露提供了新的标记，并促进了新的治疗干预措施的发展。

Exposure to environmental factors e.g. tobacco smoke, chemicals, air pollutants and nutrition can adversely affect human health. This can result in alterations to ‘chemical tags’ which normally exist on our DNA. These tags correspond to 'epigenetic marks'(on top of DNA) that can act as a ‘barcode’ of DNA function by indicating if genes are in an active or silent barcode state. Variations in the barcode can represent environmental induced changes in gene expression that have downstream adverse effects on the way cells and tissues work. This may result in enhanced disease susceptibility, for example resulting in an increase in cancer incidence or be linked with premature ageing processes. In this project we will study the contribution of epigenetic marks in regulating gene expression. Embryonic stem cells (ESCs) are models for early mouse development that can be grown in a petri dish under different culture conditions that either promote their continuous regeneration or alternatively coax them to differentiate into specific tissue types such as neural tissue. Of great interest is that one the chemical tags, 5-methylcytosine (5mC), undergoes programmed changes that are indicative of differentiation state and gene expression profiles. We will study how the lack of key enzymes (DNA methyltransferases (Dnmts)), which are important in DNA methylation reprogramming, affects ESC differentiation. Using appropriate model systems, we will undertake a detailed analysis to determine how lack of the Dnmt enzymes alters the ability of cells to differentiate normally. We use high resolution molecular profiling and imaging techniques to gain a better understanding of the contribution of epigenetics to development and by implication disease states. These studies underpin the new development of powerful diagnostic tests for disease, provide new markers for monitoring environmental exposure and promote the development of novel therapeutic interventions.