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

多梳族基因在成体干细胞及其扩增中的作用

基本信息

批准号：
16390080
负责人：
TAKIHARA Yoshihiro
金额：
$ 9.54万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390080/
关键词：
Polycomb-group genes stem cells stemness molecular basis genetically engineered mice retrovirus vector 成体幹細胞造血幹細胞 DNA複製制御 Geminin Cdt1

项目摘要

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

目前，造血干细胞(HSC)移植是治疗恶性血液病和骨髓衰竭患者的常规方法。而利用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也得到了开发，引起了对造血干细胞的进一步关注。然而，调控HSCs的分子机制仍不清楚。在本研究中，我们试图通过对多梳基因的研究，揭示果蝇发育过程中多梳基因(PcG)作为支持细胞记忆系统的基因。我们首次报道PcG是维持HSC活动所必需的。虽然最近报道PcG通过对编码p16CDKI和p19ARF的Ink4a基因的抑制作用来支持严厉，但到目前为止，支持严厉的PcG功能的分子基础还不完全清楚。我们发现了…在缺乏PcG的小鼠中，DNA复制的更多T许可受损。而PcG复合体通过PcG的成员Scmhl与DNA复制许可因子CDtl的抑制剂Ginin相互作用，我们最初根据哺乳动物中保守的蛋白质结构确定了PcG。此外，我们还通过逆转录病毒介导的基因转移方法，详细研究了HSCs中受影响的Ginin调控对HSCs的影响。结果表明，PcG复合体通过泛素化在蛋白质水平上调节Ginin，并且Ginin调节在造血和HSC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。而PcG复合体在双子座的调节中起着至关重要的作用。现在，利用体外重组系统对PcG复合体进行进一步的详细分析正在进行中。这些发现可能有助于干细胞再生医学的未来发展。较少