ELF5-controlled transcriptional networks define stem cell potency and differentiation in the trophoblast compartment

ELF5控制的转录网络定义了滋养层室中干细胞的效力和分化

• 批准号: BB/I008764/1
• 负责人: Myriam Hemberger
• 金额: $ 49.25万
• 依托单位: Babraham Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI008764%2F1
• 关键词: ELF5; controlled; transcriptional; networks; define

Lay summary (4000 chrs) Stem cells are cells that have the potential to reproduce themselves ('self-renew') as well as to form various terminally differentiated cell types of the body. For this reason stem cells are of high interest for biomedical research and regenerative medicine. We are particularly interested in stem cells that contribute exclusively to tissues of the placenta (so-called trophoblast stem cells). These stem cells are of enormous value to study developmental processes at the earliest stages of pregnancy where biological material is not available from humans. In the longer term they may also prove to be valuable for the treatment of pregnancy disorders many of which are based on a defective function of the placenta, i.e. the organ that mediates all nutrition and oxygen supply to the growing baby. A key question is how the expansion and then differentiation of this particular stem cell type is regulated to ensure the formation of a fully functional placenta. The importance of this question is further reinforced by the fact that residual trophoblast stem cells pose a tremendous risk of aggressive tumour formation in the uterus of the mother. We have identified that this mechanism may be self-controlled by a specific molecule that regulates the activity of placental genes, the transcription factor ELF5. This project investigates the molecular basis how ELF5 promotes both, trophoblast stem cell self-renewal as well as differentiation into specific placental cell types. This molecular 'switch' function between promoting the expansion of a specific stem cell population followed by triggering their terminal differentiation is of fundamental importance for a healthy pregnancy (for both mother and baby). It may also prove to be translatable into other cell and organ systems where this molecule is present and that are particularly susceptible to an imbalance between proliferation and differentiation, such as the breast with its susceptibility to develop cancer. Hence understanding the mechanism of ELF5 function may establish a paradigm for molecular pathways that ensure normal reproduction as well as health throughout adult life and ageing.

分层摘要（4000个CHRS）干细胞是具有繁殖（“自我更新”）并形成人体各种末端分化的细胞类型的细胞。因此，干细胞对生物医学研究和再生医学具有很高的兴趣。我们对仅对胎盘组织（所谓的滋养细胞干细胞）贡献的干细胞特别感兴趣。这些干细胞在最早的妊娠阶段研究发育过程具有巨大的价值，而人类无法获得生物材料。从长远来看，它们也可能被证明对于治疗妊娠障碍的有价值，其中许多是基于胎盘的缺陷功能，即介导所有营养和氧气供应的器官。一个关键的问题是如何调节这种特定干细胞类型的扩展和区分以确保形成功能齐全的胎盘。残留的滋养细胞干细胞在母亲子宫中构成侵袭性肿瘤形成的巨大风险，进一步加强了这个问题的重要性。我们已经确定，这种机制可以由调节胎盘基因活性（转录因子ELF5）的特定分子自控。该项目研究了ELF5如何促进滋养层干细胞自我更新以及分化为特定胎盘细胞类型的分子基础。在促进特定干细胞种群的扩展之后，触发其末端分化的这种分子“转换”功能对于健康怀孕至关重要（对于母亲和婴儿）。它也可能被证明可以翻译成该分子存在的其他细胞和器官系统，并且特别容易受到增殖和分化之间的不平衡，例如具有易感癌症的乳房。因此，了解ELF5功能的机制可能会为分子途径建立一个范式，以确保在整个成人生活和衰老中确保正常繁殖以及健康。

项目成果

Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells.

• DOI: 10.1038/ncomms8776
• 发表时间: 2015-07-24
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Latos PA;Goncalves A;Oxley D;Mohammed H;Turro E;Hemberger M
• 通讯作者: Hemberger M

The Guide of Investigations of Mouse Pregnancy

小鼠妊娠调查指南

• 发表时间: 2013
• 作者: Hemberger, M.;Dean, W.
• 通讯作者: Dean, W.

Epigenetic memory of the first cell fate decision prevents complete ES cell reprogramming into trophoblast.

• DOI: 10.1038/ncomms6538
• 发表时间: 2014-11-26
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Cambuli, Francesco;Murray, Alexander;Dean, Wendy;Dudzinska, Dominika;Krueger, Felix;Andrews, Simon;Senner, Claire E.;Cook, Simon J.;Hemberger, Myriam
• 通讯作者: Hemberger, Myriam

Derivation and maintenance of murine trophoblast stem cells under defined conditions.

• DOI: 10.1016/j.stemcr.2013.12.013
• 发表时间: 2014-02-11
• 期刊: STEM CELL REPORTS
• 影响因子: 5.9
• 作者: Kubaczka, Caroline;Senner, Claire;Arauzo-Bravo, Marcos J.;Sharma, Neha;Kuckenberg, Peter;Becker, Astrid;Zimmer, Andreas;Bruestle, Oliver;Peitz, Michael;Hemberger, Myriam;Schorle, Hubert
• 通讯作者: Schorle, Hubert

Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry-sensitive shifts in target gene networks.

• DOI: 10.1101/gad.268821.115
• 发表时间: 2015-12-01
• 期刊: Genes & development
• 影响因子: 10.5
• 作者: Latos PA;Sienerth AR;Murray A;Senner CE;Muto M;Ikawa M;Oxley D;Burge S;Cox BJ;Hemberger M
• 通讯作者: Hemberger M