Promoter-associated histone modifications and establishment of the developmental gene expression program during early embryogenesis

包括人类在内的动物身体都是由一个受精卵细胞发育而来。受精卵的胚胎发育是通过胚胎细胞的增殖和这些细胞的一系列协调变化而发生的，这些变化导致了各种组织的形成。这个过程是由数千个基因在正确的时间和正确的细胞中协调激活所控制的，被称为发育的遗传调控。每个细胞都携带相同的一组基因，但基因的活性在不同的细胞类型中差异很大。基因何时何地开启是正常发育的关键决定因素，并被编码在每个细胞中存在的DNA序列中。然而，还有一种额外的基因控制机制，它通过细胞核中DNA（基因及其开关）的选择性包装来运作。DNA的包装（称为染色质）因细胞而异，对标记激活基因很重要。DNA包装的标记和顺序在细胞增殖过程中在细胞间遗传，也可能在受精后从卵母细胞和精子遗传。这一过程被称为表观遗传，对遗传信息如何从亲本传递到胚胎具有重要意义。在这个项目中，我们将研究一种特殊类型的表观遗传信息如何有助于胚胎发育过程中的基因调控。我们将使用一种小型动物模型斑马鱼，由于鱼类和人类胚胎在发育过程中调节其基因的方式相似，并且由于小型透明鱼胚胎易于在实验室条件下培养和监测，因此斑马鱼在发育遗传分析中很受欢迎。我们将研究在DNA包装中重要的蛋白质（组蛋白）如何在配子和胚胎中被标记，以了解它们是否对从父母向发育中的胚胎传递表观遗传信息很重要。我们将通过生化分析来探索表观遗传调控的DNA编码，这将告诉我们基因开关上的组蛋白标记，并通过分析在胚胎发育过程中活跃的基因开关位置携带DNA包装编码的DNA序列。我们的发现对于理解正常发育过程中基因的调控非常重要，对于那些研究导致发育和成人生活中各种疾病的异常基因调控的原因也很有用。

Animal bodies including that of humans develop from a single cell, the fertilised egg. The development of embryos from fertilised eggs happens through proliferation of embryonic cells and a coordinated sequence of changes of these cells, which leads to formation of a variety of tissues. This process is governed by the coordinated activation of thousands of genes at the right time and in the right cells and is called genetic regulation of development. Each of the cells carry the same set of genes yet the activity of genes varies greatly in various cell types. When and where genes get switched on is a key determinant of normal development and is encoded in the DNA sequence present in every cell. However, there is an additional mechanism of gene control, which operates by selective packaging of DNA (the genes and their switches) in the cell nucleus. The packaging of DNA (called chromatin) varies between cells and is important for marking the genes for activation. The marking and order of DNA packaging is inherited between cells during cell proliferation and may also be inherited from the oocyte and the sperm after fertilisation. This process is called epigenetic inheritance and has important implications in how inherited information is conveyed from parent to the embryo. In this project we will study how one particular type of epigenetic information may contribute to the regulation of genes during embryo development. We will use a small animal model zebrafish, which is popular for genetic analysis of development due to the similarities in the way fish and human embryos regulate their genes during development and because the small transparent fish embryos can be easily cultured and monitored in laboratory conditions. We will study how proteins important in DNA packaging (histones) are marked in gametes and embryos to ask whether they are important for conveying epigenetic information from the parents to the developing embryo. We will explore the DNA codes of epigenetic regulation using biochemical assays that will tell us about histone marks on gene switches, and by analysing the DNA sequences which carry the codes for DNA packaging at the sites of the switches of genes active during embryo development. Our findings will be important for understanding the regulation of genes in normal development and will be useful for those studying the reasons for abnormal gene regulation, which causes a variety of disease both in development and in adult life.