Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
Cell Stem Cell. 2010 Mar 5;6(3):279-86. doi: 10.1016/j.stem.2010.01.005.
Polycomb group (PcG) proteins are essential regulators of stem cells. PcG and trithorax group proteins mark developmental regulator gene promoters with bivalent domains consisting of overlapping repressive and activating histone modifications to keep them poised for activation in embryonic stem cells. Bmi1, a component of PcG complexes, maintains the self-renewal capacity of adult stem cells, but its role in multipotency remains obscure. Here we show that Bmi1 is critical for multipotency of hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs). B cell lineage developmental regulator genes, Ebf1 and Pax5, appeared to be transcriptionally repressed by bivalent domains before lineage commitment. Loss of Bmi1 resulted in a resolution of bivalent domains at the Ebf1 and Pax5 loci, leading to their premature expression in HSC/MPPs accompanied by accelerated lymphoid specification and a marked reduction in HSC/MPPs. Thus, Bmi1 is required to reinforce bivalent domains at key developmental regulator gene loci to maintain lineage specification poised for activation in adult stem cells.
多梳抑制复合物（PcG）蛋白是干细胞的重要调节因子。PcG 和 trithorax 组蛋白修饰酶复合物蛋白通过在发育调控基因启动子上形成包含重叠抑制性和激活型组蛋白修饰的双价结构域来标记它们，使它们在胚胎干细胞中处于激活状态。Bmi1 是 PcG 复合物的一个组成部分，维持着成体干细胞的自我更新能力，但它在多能性中的作用仍不清楚。在这里，我们发现 Bmi1 对于造血干细胞（HSCs）和多能祖细胞（MPPs）的多能性至关重要。在谱系定向之前，B 细胞谱系发育调控基因 Ebf1 和 Pax5 似乎被双价结构域转录抑制。Bmi1 的缺失导致 Ebf1 和 Pax5 基因座上双价结构域的分辨率提高，导致它们在 HSC/MPPs 中过早表达，伴随淋巴样细胞特异性的加速和 HSC/MPPs 的显著减少。因此，Bmi1 需要加强关键发育调控基因座上的双价结构域，以维持成体干细胞中处于激活状态的谱系特异性。
