Maytum Alexander, Edginton-White Ben, Bonifer Constanze
Institute of Cancer and Genomic Sciences, School of Medicine and Dentistry, University of Birmingham, Birmingham, UK.
Stem Cell Investig. 2023 Jun 25;10:14. doi: 10.21037/sci-2023-011. eCollection 2023.
The development of multi-cellular organisms from a single fertilized egg requires to differentially execute the information encoded in our DNA. This complex process is regulated by the interplay of transcription factors with a chromatin environment, both of which provide the epigenetic information maintaining cell-type specific gene expression patterns. Moreover, transcription factors and their target genes form vast interacting gene regulatory networks which can be exquisitely stable. However, all developmental processes originate from pluripotent precursor cell types. The production of terminally differentiated cells from such cells, therefore, requires successive changes of cell fates, meaning that genes relevant for the next stage of differentiation must be switched on and genes not relevant anymore must be switched off. The stimulus for the change of cell fate originates from extrinsic signals which set a cascade of intracellular processes in motion that eventually terminate at the genome leading to changes in gene expression and the development of alternate gene regulatory networks. How developmental trajectories are encoded in the genome and how the interplay between intrinsic and extrinsic processes regulates development is one of the major questions in developmental biology. The development of the hematopoietic system has long served as model to understand how changes in gene regulatory networks drive the differentiation of the various blood cell types. In this review, we highlight the main signals and transcription factors and how they are integrated at the level of chromatin programming and gene expression control. We also highlight recent studies identifying the -regulatory elements such as enhancers at the global level and explain how their developmental activity is regulated by the cooperation of cell-type specific and ubiquitous transcription factors with extrinsic signals.
从单个受精卵发育成多细胞生物需要差异化地执行我们DNA中编码的信息。这个复杂的过程由转录因子与染色质环境的相互作用来调控，二者都提供维持细胞类型特异性基因表达模式的表观遗传信息。此外，转录因子及其靶基因形成了庞大的相互作用基因调控网络，这些网络可以极其稳定。然而，所有发育过程都起源于多能前体细胞类型。因此，从这些细胞产生终末分化细胞需要细胞命运的连续变化，这意味着与下一阶段分化相关的基因必须开启，而不再相关的基因必须关闭。细胞命运改变的刺激源自外部信号，这些信号启动一系列细胞内过程，最终在基因组处终止，导致基因表达的变化和交替基因调控网络的发育。发育轨迹如何在基因组中编码，以及内在和外在过程之间的相互作用如何调节发育，是发育生物学中的主要问题之一。造血系统的发育长期以来一直作为模型，用于理解基因调控网络的变化如何驱动各种血细胞类型的分化。在这篇综述中，我们强调了主要信号和转录因子，以及它们如何在染色质编程和基因表达控制水平上整合。我们还强调了最近在全球层面鉴定调控元件（如增强子）的研究，并解释了它们的发育活性如何通过细胞类型特异性和普遍存在的转录因子与外部信号的合作来调控。
