Vidal Miguel, Starowicz Katarzina
Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas, Madrid, Spain.
Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas, Madrid, Spain.
Exp Hematol. 2017 Apr;48:12-31. doi: 10.1016/j.exphem.2016.12.006. Epub 2017 Jan 10.
Hematopoiesis, the process by which blood cells are continuously produced, is one of the best studied differentiation pathways. Hematological diseases are associated with reiterated mutations in genes encoding important gene expression regulators, including chromatin regulators. Among them, the Polycomb group (PcG) of proteins is an essential system of gene silencing involved in the maintenance of cell identities during differentiation. PcG proteins assemble into two major types of Polycomb repressive complexes (PRCs) endowed with distinct histone-tail-modifying activities. PRC1 complexes are histone H2A E3 ubiquitin ligases and PRC2 trimethylates histone H3. Established conceptions about their activities, mostly derived from work in embryonic stem cells, are being modified by new findings in differentiated cells. Here, we focus on PRC1 complexes, reviewing recent evidence on their intricate architecture, the diverse mechanisms of their recruitment to targets, and the different ways in which they engage in transcriptional control. We also discuss hematopoietic PRC1 gain- and loss-of-function mouse strains, including those that model leukemic and lymphoma diseases, in the belief that these genetic analyses provide the ultimate test for molecular mechanisms driving normal hematopoiesis and hematological malignancies.
造血作用,即血细胞持续产生的过程,是研究最为深入的分化途径之一。血液学疾病与编码重要基因表达调节因子(包括染色质调节因子)的基因反复突变有关。其中,多梳蛋白家族(PcG)蛋白是一种重要的基因沉默系统,参与分化过程中细胞身份的维持。PcG蛋白组装成两种主要类型的多梳抑制复合物(PRC),具有不同的组蛋白尾部修饰活性。PRC1复合物是组蛋白H2A E3泛素连接酶,PRC2使组蛋白H3三甲基化。关于它们活性的既定概念,大多源自胚胎干细胞研究工作,而分化细胞中的新发现正在对这些概念进行修正。在此,我们聚焦于PRC1复合物,回顾有关其复杂结构、招募至靶标的多种机制以及参与转录调控的不同方式的最新证据。我们还讨论了造血PRC1功能获得和功能丧失小鼠品系,包括那些模拟白血病和淋巴瘤疾病的品系,因为我们相信这些遗传学分析为驱动正常造血和血液系统恶性肿瘤的分子机制提供了最终检验。