Establishment of the haemopoietic transcriptional programme: From systems approaches to molecular mechanisms

造血转录程序的建立：从系统方法到分子机制

• 批准号: BB/I00050X/1
• 负责人: Berthold Gottgens
• 金额: $ 115.26万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI00050X%2F1
• 关键词: Establishment; haemopoietic; transcriptional; programme; systems

Our genes control how our body develops from one fertilized egg cell and all cells in our body contain the same set of genes. This cell rapidly divides and develops into a large variety of distinct cell types that make up the various organs in our body. All these cells express different genetic programs, meaning that not all of our genes are always active in every cell type. This cell-type-specific gene activation pattern is governed by another layer of control (on top of the layer of the genes) that tells cells which genes to switch on and off, thereby deciding which cell type develops. This additional control layer is called the 'epigenetic' layer and consists of two components: (1) a genome-wide network through which genes regulate each other to generate the appropriate gene expression patterns; (2) the DNA packing apparatus. Each cell contains one meter of DNA, and to be able to fit it into the nucleus, it is densely compacted by so called chromatin proteins such that inactive genes are highly compact and their DNA hidden, whereas active genes are in areas of reduced compaction. To activate an inactive, compact gene, protein complexes, so called 'transcription factors' push chromatin aside or modify it, so that genes become accessible to the factors that activate them. Studies in the past years focused on one gene at a time and led to the discovery of the transcription factors and chromatin components that control their activity. We learned to extract the tune that individual genes play but failed to hear the symphony. Our understanding of how all the genes in mammals are orchestrated to switch on and off in the right order is still superficial. Moreover, much of what we know is based on studies from cell lines, which represent fixed cell types or are cancer cells, and from simpler organisms, such as yeast. The situation in mammals is much more complex because building an organism from a fertilized egg involves turning one cell type into another (so called 'differentiation') in a precise hierarchical order which requires tight coordination of the activity of all the genes. In other words, building an organism is like building a house: we have to put the individual components together in a precise order and not start with the roof before the cellar. This proposal will use blood cell development in the mouse as a model to investigate the dynamics of cell differentiation in mammals. We will study all genes of a given cell type and use a sophisticated in vitro system based on embryonic stem cells where we can generate and purify different blood cell types. We then will identify which transcription factors and chromatin components regulate which genes at the different developmental stages and study at which level and when they are expressed. Until recently such global or 'systems biology' studies were beyond reach since the technology was lacking. However, with the latest technology we can determine the entire DNA sequence of one cell type in a very short time. This technology has been modified to study epigenetic changes at all genes and can now be used to identify what distinguishes genes of one cell type from those of another. However, one feature of such experiments is that they produce enormous amounts of data and require specialist knowledge to make sense of them. This is achieved by bioinformaticians developing new computer programs and mathematical modelers running simulations to predict the integrated, 'collective' behavior of genes. To this end we have formed an interdisciplinary consortium consisting of experimental researchers and computational biologists who will collaborate to understand how thousands of genes work together to generate specific cell types. The ultimate aim of these studies is to be able to understand how individual development is encoded in the DNA-sequence and to predict how changes in the DNA sequence impact on developmental processes.

我们的基因控制着我们的身体如何从一个受精卵细胞发育而来，并且我们体内的所有细胞都包含相同的一组基因。这种细胞迅速分裂并发育成多种不同的细胞类型，构成我们体内的各种器官。所有这些细胞都表达不同的遗传程序，这意味着并非所有基因在每种细胞类型中都始终活跃。这种细胞类型特异性的基因激活模式由另一层控制（在基因层之上）控制，该控制层告诉细胞打开和关闭哪些基因，从而决定哪种细胞类型发育。这个额外的控制层称为“表观遗传”层，由两个部分组成：（1）全基因组网络，基因通过该网络相互调节以生成适当的基因表达模式； (2)DNA包装装置。每个细胞都含有一米长的 DNA，为了能够将其装入细胞核，它被所谓的染色质蛋白紧密压缩，这样不活跃的基因高度紧凑，其 DNA 被隐藏，而活跃的基因则位于压缩程度较低的区域。为了激活不活跃的紧凑基因，蛋白质复合物（所谓的“转录因子”）将染色质推到一边或对其进行修改，以便基因可以被激活它们的因子所接近。过去几年的研究一次集中于一个基因，并发现了控制其活性的转录因子和染色质成分。我们学会了提取单个基因演奏的曲调，但未能听到交响乐。我们对哺乳动物的所有基因如何按照正确的顺序启动和关闭的理解仍然很肤浅。此外，我们所知道的大部分知识都是基于对细胞系（代表固定细胞类型或癌细胞）以及更简单的生物体（例如酵母）的研究。哺乳动物的情况要复杂得多，因为从受精卵构建有机体涉及到以精确的层次顺序将一种细胞类型转变为另一种细胞类型（所谓的“分化”），这需要所有基因活动的紧密协调。换句话说，建造一个有机体就像建造一座房子：我们必须按照精确的顺序将各个组件组装在一起，而不是先从屋顶开始，然后再从地窖开始。该提案将使用小鼠血细胞发育作为模型来研究哺乳动物细胞分化的动态。我们将研究给定细胞类型的所有基因，并使用基于胚胎干细胞的复杂体外系统，在其中我们可以生成和纯化不同的血细胞类型。然后，我们将确定哪些转录因子和染色质成分在不同发育阶段调节哪些基因，并研究它们在哪个水平以及何时表达。直到最近，由于缺乏技术，这种全球性或“系统生物学”研究仍然遥不可及。然而，利用最新技术，我们可以在很短的时间内确定一种细胞类型的整个 DNA 序列。这项技术经过修改，可以研究所有基因的表观遗传变化，现在可以用来识别一种细胞类型的基因与另一种细胞类型的基因的区别。然而，此类实验的一个特点是它们会产生大量数据，并且需要专业知识才能理解它们。这是通过生物信息学家开发新的计算机程序和数学建模者运行模拟来预测基因的综合“集体”行为来实现的。为此，我们成立了一个由实验研究人员和计算生物学家组成的跨学科联盟，他们将合作了解数千个基因如何协同工作以产生特定的细胞类型。这些研究的最终目的是了解 DNA 序列如何编码个体发育，并预测 DNA 序列的变化如何影响发育过程。

项目成果

The transcription factor Erg regulates expression of HDAC6 and multiple pathways involved in endothelial cell migration and angiogenesis

转录因子 Erg 调节 HDAC6 的表达以及参与内皮细胞迁移和血管生成的多种途径

• DOI: http://dx.10.1016/j.vph.2011.08.120
• 发表时间: 2012
• 期刊: Vascular Pharmacology
• 影响因子: 4
• 作者: Birdsey G

Genome scale transcriptional control of haematopoietic cell type identity

造血细胞类型识别的基因组规模转录控制

• DOI: http://dx.10.1016/j.exphem.2013.05.269
• 发表时间: 2013
• 期刊: Experimental Hematology
• 影响因子: 2.6
• 作者: Calero

Genome-wide analysis of transcriptional regulators in human HSPCs reveals a densely interconnected network of coding and noncoding genes.

对人类 HSPC 转录调节因子的全基因组分析揭示了编码和非编码基因的紧密互连网络。

• DOI: 10.1182/blood-2013-03-490425
• 发表时间: 2013-10-03
• 期刊: Blood
• 影响因子: 20.3
• 作者: D. Beck;J. Thoms;Dilmi Perera;J. Schütte;Ashwin Unnikrishnan;K. Knezevic;S. Kinston;Nicola K. Wilson;T. O'Brien;B. Göttgens;J. Wong;J. Pim;a;a
• 通讯作者: a

The endothelial transcription factor ERG promotes vascular stability and growth through Wnt/ß-catenin signaling.

内皮转录因子 ERG 通过 Wnt/β-连环蛋白信号传导促进血管稳定性和生长。

• DOI: http://dx.10.1016/j.devcel.2014.11.016
• 发表时间: 2015
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Birdsey GM

The transcription factor Erg regulates expression of histone deacetylase 6 and multiple pathways involved in endothelial cell migration and angiogenesis.

转录因子 Erg 调节组蛋白脱乙酰酶 6 的表达以及参与内皮细胞迁移和血管生成的多种途径。

• DOI: 10.1182/blood-2011-04-350025
• 发表时间: 2012-01-19
• 期刊: Blood
• 影响因子: 20.3
• 作者: G. Birdsey;N. Dryden;Aarti Shah;R. Hannah;M. Hall;D. Haskard;M. Parsons;J. Mason;M. Zvelebil;Berthold Gottgens;A. Ridley;A. R;i;i
• 通讯作者: i