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.

干细胞是具有自我复制（“自我更新”）以及形成身体的各种终末分化细胞类型的潜力的细胞。由于这个原因，干细胞在生物医学研究和再生医学中具有很高的兴趣。我们特别感兴趣的是专门为胎盘组织（所谓的滋养层干细胞）贡献的干细胞。这些干细胞对于研究妊娠早期的发育过程具有巨大的价值，因为在妊娠早期，人类无法获得生物材料。从长远来看，它们也可能被证明对治疗妊娠障碍有价值，其中许多是基于胎盘的功能缺陷，即为生长中的婴儿提供所有营养和氧气供应的器官。一个关键问题是如何调节这种特定干细胞类型的扩增和分化，以确保形成功能齐全的胎盘。这个问题的重要性进一步加强了这一事实，即残留的滋养层干细胞构成了巨大的风险，积极的肿瘤形成在子宫的母亲。我们已经确定，这种机制可能是自我控制的一个特定的分子，调节胎盘基因的活性，转录因子ELF 5。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。在促进特定干细胞群体的扩增之后触发其终末分化之间的这种分子“开关”功能对于健康怀孕（对于母亲和婴儿）具有根本重要性。它也可能被证明可以转移到其他细胞和器官系统中，在这些系统中存在这种分子，并且特别容易受到增殖和分化之间不平衡的影响，例如乳腺癌。因此，了解ELF5功能的机制可能会为确保正常生殖以及整个成年生活和衰老过程中的健康的分子途径建立一个范例。

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.

第一个细胞命运决策的表观遗传记忆可防止ES细胞重编程为滋养细胞。

• 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