Opposing roles of polycomb repressive complexes in hematopoietic stem and progenitor cells
Opposing roles of polycomb repressive complexes in hematopoietic stem and progenitor cells
复制标题
DOI：
10.1182/blood-2009-12-260760
复制
发表时间：
2010-08-05
期刊：
影响因子：
20.3
通讯作者：
Blewitt, Marnie E.
中科院分区：
文献类型：
--
作者：
Majewski, Ian J.;Ritchie, Matthew E.;Blewitt, Marnie E.
Polycomb group（PcG）蛋白是转录抑制因子，在发育过程中基因表达模式的建立和维持中起着重要作用。我们研究了多梳抑制复合物（PRCs）在造血干细胞（HSC）和祖细胞群体中的作用。我们发现PRC 2组分功能缺失突变的小鼠显示出增强的HSC/祖细胞群体活性，而破坏PRC 1或多同源异型抑制复合物的突变与HSC/祖细胞缺陷相关。因为PRC作用的分级模型将预测PRC 1和PRC 2突变的协同效应，这些相反的效应表明该模型在HSC/祖细胞中不成立。为了研究HSC/祖细胞中每个复合物的分子靶点，我们测量了与PRC缺陷相关的全基因组表达变化，并确定了由PRC 1和PRC 2差异调节的转录网络。这些研究为不同PRC之间的机制相互作用提供了新的见解，并对接近PcG蛋白作为治疗靶点具有重要意义。（血。2010; 116（5）：731-739）
Polycomb group (PcG) proteins are transcriptional repressors with a central role in the establishment and maintenance of gene expression patterns during development. We have investigated the role of polycomb repressive complexes (PRCs) in hematopoietic stem cells (HSCs) and progenitor populations. We show that mice with loss of function mutations in PRC2 components display enhanced HSC/progenitor population activity, whereas mutations that disrupt PRC1 or pleiohomeotic repressive complex are associated with HSC/progenitor cell defects. Because the hierarchical model of PRC action would predict synergistic effects of PRC1 and PRC2 mutation, these opposing effects suggest this model does not hold true in HSC/progenitor cells. To investigate the molecular targets of each complex in HSC/progenitor cells, we measured genome-wide expression changes associated with PRC deficiency, and identified transcriptional networks that are differentially regulated by PRC1 and PRC2. These studies provide new insights into the mechanistic interplay between distinct PRCs and have important implications for approaching PcG proteins as therapeutic targets. (Blood. 2010; 116(5):731-739)