Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Kobe, Japan.
Dev Biol. 2012 Jun 15;366(2):404-19. doi: 10.1016/j.ydbio.2012.03.024. Epub 2012 Apr 21.
Transcription factors have long been recognised as powerful regulators of mammalian development yet it is largely unknown how individual key regulators operate within wider regulatory networks. Here we have used a combination of global gene expression and chromatin-immunoprecipitation approaches during the early stages of haematopoietic development to define the transcriptional programme controlled by Runx1, an essential regulator of blood cell specification. Integrated analysis of these complementary genome-wide datasets allowed us to construct a global regulatory network model, which suggested that key regulators are activated sequentially during blood specification, but will ultimately collaborate to control many haematopoietically expressed genes. Using the CD41/integrin alpha 2b gene as a model, cellular and in vivo studies showed that CD41 is controlled by both Scl/Tal1 and Runx1 in fully specified blood cells, and initiation of CD41 expression in E7.5 embryos is severely compromised in the absence of Runx1. Taken together, this study represents the first global analysis of the transcriptional programme controlled by any key haematopoietic regulator during the process of early blood cell specification. Moreover, the concept of interplay between sequentially deployed core regulators is likely to represent a design principle widely applicable to the transcriptional control of mammalian development.
转录因子长期以来一直被认为是哺乳动物发育的强大调节剂，但人们对单个关键调节剂如何在更广泛的调节网络中发挥作用知之甚少。在这里，我们在造血发育的早期阶段结合使用了全局基因表达和染色质免疫沉淀方法，以定义由 Runx1 控制的转录程序，Runx1 是血细胞特化的必需调节剂。对这些互补的全基因组数据集的综合分析使我们能够构建一个全局调控网络模型，该模型表明关键调节剂在血液特化过程中按顺序激活，但最终将共同控制许多造血表达基因。使用 CD41/整合素 α2b 基因作为模型，细胞和体内研究表明，CD41 由 Scl/Tal1 和 Runx1 共同控制，在完全特化的血细胞中，并且在缺乏 Runx1 的情况下，E7.5 胚胎中 CD41 的表达起始严重受损。总之，这项研究代表了对任何关键造血调节剂在早期血细胞特化过程中控制的转录程序的首次全面分析。此外，核心调节剂之间相互作用的概念可能代表一个广泛适用于哺乳动物发育转录控制的设计原则。
