Role of Polycomb-group genes in adult stem cells and their expansion

造血干细胞（HSC）移植目前在临床实践中用于治疗血液病恶性肿瘤和骨髓衰竭患者。随着造血干细胞治疗其他恶性肿瘤和包括心肌梗死在内的血管衰竭患者的新策略的发展，造血干细胞引起了人们的进一步关注。然而，调节造血干细胞的分子机制仍不清楚。在这项研究中，我们以Polycomb-group基因为重点，试图揭示严厉的潜在作用。Polycomb-group基因（Polycomb-group genes, PcG）是果蝇发育过程中支持细胞记忆系统的基因。我们首次报道了PcG是维持HSC活性所必需的。尽管最近有报道称PcG通过抑制编码p16CDKI和p19ARF的ink4A基因座的活性来支持严厉性，但迄今为止，支持严厉性的PcG功能的分子基础尚未完全了解。我们发现，在缺乏PcG的小鼠中，更多的DNA复制许可受到损害。PcG复合物与Geminin相互作用，Geminin是一种DNA复制许可因子Cdtl的抑制剂，通过PcG成员Scmhl相互作用，我们最初根据哺乳动物的保守蛋白质结构确定了PcG。我们还发现Hoxb4，一个众所周知的调节hsc的因子，也与Geminin相互作用。此外，通过逆转录病毒介导的基因转移方法，我们详细检查了受影响的Geminin调控对hsc的影响。我们发现PcG复合物通过泛素化在蛋白质水平上调节Geminin，而Geminin的调节在造血和HSC的调节中是关键的。这些结果表明，DNA复制许可是维持HSC活性的关键。PcG复合物在gemini的调控中起着至关重要的作用。目前，利用体外重组系统对PcG复合物进行了更详细的分析。这些发现可能有助于干细胞再生医学的未来发展。少

Hematopoietic stem cell (HSC) transplantation is now routinely performed in clinical practice for the treatment of patients with hematological malignancies and bone marrow failure. And new strategies with HSCs are developed for the treatment of patients with the other malignancies and vascular failure including myocardial infarction, attracting further attention to HSCs. However, molecular mechanisms regulating HSCs still remain unclear.In this study, focusing on Polycomb-group genes we attempted to uncover the role underlying sternness.Polycomb-group genes (PcG) were uncovered by Drosophila genetics as genes supporting the cellular memory system during development. We for the first time reported that PcG are required for sustaining HSC activity. Although PcG are recently reported to support sternness through the repression activity to ink4A locus encoding p16CDKI and p19ARF, so far the molecular bases underlying PcG functions supporting sternness are not fully understood. We found tha … More t licensing of DNA replication was impaired in mice lacking PcG. And PcG complexes interact with Geminin, an inhibitor of a DNA replication licensing factor Cdtl through Scmhl, a member of PcG, which we originally identified based on the conserved protein structure in mammals. We also found Hoxb4, a well known factor regulating HSCs, also interacts with Geminin.Furthermore, by using retrovirus-mediated gene transfer method, we examined in detail the effect of affected Geminin regulation on HSCs. And we showed that PcG complexes regulate Geminin at the level of protein through ubiquitination and that Geminin regulation is pivotal in hematopoiesis and HSC regulation.These results indicate that DNA replication licensing is pivotal in sustaining HSC activity. And PcG complexes play a crucial role in regulation of Geminin. Now by using in vitro reconstituting system further detailed analysis of PcG complexes are in progress. These findings may help future progress in regenerative medicine with stem cells. Less