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

造血干细胞（HSC）移植是目前临床上治疗恶性血液病和骨髓衰竭的常规方法。近年来，造血干细胞在治疗其他恶性肿瘤和心肌梗死等血管功能衰竭患者中的应用越来越受到人们的关注。然而，调控HSC的分子机制仍不清楚，本研究以果蝇遗传学发现的支持细胞记忆系统的多梳基因（Polycomb-group genes，PcG）为研究对象，试图揭示其在干细胞中的作用。我们首次报道了PcG是维持HSC活性所必需的。虽然最近报道PcG通过对编码p16 CDKI和p19 ARF的ink 4A位点的抑制活性支持干性，但迄今为止，PcG支持干性的分子基础尚未完全了解。我们发现， ...更多信息 在缺乏PcG的小鼠中，DNA复制的t许可受损。PcG复合物通过Scmhl与Geminin相互作用，Geminin是DNA复制许可因子Cdtl的抑制剂，Scmhl是我们最初根据哺乳动物中保守的蛋白质结构鉴定的PcG成员。我们还发现Hoxb 4与Geminin也存在相互作用，并通过逆转录病毒介导的基因转移方法，详细研究了Geminin对HSC的调控作用。我们发现PcG复合物通过泛素化在蛋白质水平上调节Geminin，并且Geminin的调节在造血和HSC的调节中起关键作用，这些结果表明DNA复制许可在维持HSC活性中起关键作用。PcG复合物在Geminin的调节中起着重要的作用。目前正在利用体外重组系统对PcG复合物进行更详细的分析。这些发现可能有助于干细胞再生医学的未来进展。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