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

早期胚胎发生过程中启动子相关的组蛋白修饰和发育基因表达程序的建立

• 批准号: BB/L010488/1
• 负责人: Ferenc Mueller
• 金额: $ 48.08万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL010488%2F1
• 关键词: Promoter; associated; histone; modifications; establishment

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.

包括人类在内的动物体是由单个细胞（受精卵）发育而来的。受精卵发育成胚胎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，从而导致各种组织的形成。这一过程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，称为发育的遗传调控。每个细胞都携带相同的基因组，但不同细胞类型的基因活性差异很大。基因何时何地开启是正常发育的关键决定因素，并且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）的选择性包装来发挥作用。 DNA 的包装（称为染色质）因细胞而异，对于标记基因的激活非常重要。 DNA包装的标记和顺序在细胞增殖过程中在细胞之间遗传，也可能在受精后从卵母细胞和精子遗传。这个过程称为表观遗传，对于遗传信息如何从亲代传递到胚胎具有重要意义。在这个项目中，我们将研究一种特定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基因的方式相似，而且小型透明鱼胚胎可以在实验室条件下轻松培养和监测，因此斑马鱼在发育遗传分析中很受欢迎。我们将研究在配子和胚胎中如何标记 DNA 包装（组蛋白）中重要的蛋白质，以了解它们对于将表观遗传信息从父母传递到发育中的胚胎是否重要。我们将利用生化分析来探索表观遗传调控的 DNA 代码，这些分析将告诉我们基因开关上的组蛋白标记，并分析携带胚胎发育过程中活跃基因开关位点 DNA 包装代码的 DNA 序列。我们的研究结果对于理解正常发育中基因的调节非常重要，并且对于研究异常基因调节的原因也很有用，异常基因调节会导致发育和成年生活中的多种疾病。

项目成果

Germ cell differentiation requires Tdrd7-dependent chromatin and transcriptome reprogramming marked by germ plasm relocalization.

• DOI: 10.1016/j.devcel.2021.02.007
• 发表时间: 2021-03-08
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: D'Orazio FM;Balwierz PJ;González AJ;Guo Y;Hernández-Rodríguez B;Wheatley L;Jasiulewicz A;Hadzhiev Y;Vaquerizas JM;Cairns B;Lenhard B;Müller F
• 通讯作者: Müller F

Transcriptional, post-transcriptional and chromatin-associated regulation of pri-miRNAs, pre-miRNAs and moRNAs.

转录，转录后和染色质相关的PRI-MIRNA，前MIRNA和MORNA的调节。

• DOI: 10.1093/nar/gkv1354
• 发表时间: 2016-04-20
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Nepal C;Coolen M;Hadzhiev Y;Cussigh D;Mydel P;Steen VM;Carninci P;Andersen JB;Bally-Cuif L;Müller F;Lenhard B
• 通讯作者: Lenhard B

Glucocorticoid deficiency causes transcriptional and post-transcriptional reprogramming of glutamine metabolism.

• DOI: 10.1016/j.ebiom.2018.09.024
• 发表时间: 2018-10
• 期刊: EBioMedicine
• 影响因子: 11.1
• 作者: Weger M;Weger BD;Görling B;Poschet G;Yildiz M;Hell R;Luy B;Akcay T;Güran T;Dickmeis T;Müller F;Krone N
• 通讯作者: Krone N