Re-defining the paradigm of X-chromosome inactivation

重新定义X染色体失活的范式

• 批准号: MR/R017735/1
• 负责人: Kevin Chalut
• 金额: $ 53.04万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR017735%2F1
• 关键词: Re; defining; paradigm; chromosome; inactivation

In humans, and most mammals, the sex of an individual is determined by the presence of a pair of sex chromosomes: XX in females, XY in males. The X chromosome carries about 800 genes which contain genetic information that is essential for the body to function. The normal, healthy 'dosage' of genes is delivered through the presence of one chromosome. In males, who carry one X and one Y chromosome (XY), this genetic dosage is naturally delivered. In females, who carry two X chromosomes (XX), the correct genetic dosage is obtained through silencing of one of their X chromosomes, in a process known as 'X-Chromosome Inactivation'. Since this discovery of X chromosome inactivation in 1961, the exact mechanisms underpinning this process have been the focus of extensive study. My group recently made the surprising discovery that males also undergo X-chromosome inactivation in early embryonic development, albeit transiently. This finding has the potential to change the scientific understanding of how X-chromosome inactivation works. In the present study, we propose to use naïve pluripotent stem cells from mice and humans to study X-chromosome inactivation. Naïve pluripotent stem cells are cells that represent the very earliest stage embryonic development, and have the ability to self-replicate exactly or to change into any cell type in the body. Our research will reveal how changes in these naïve cells at key embryonic developmental stages initiates X chromosome inactivation in both males and females. Establishing these processes is central to our understanding of early developmental stem cell biology, and will shift the current accepted paradigm that X chromosome inactivation is a female-only phenomenon. In the medical context, random reactivation of X-linked genes has been reported during ageing and in cancerous cells. Understanding the process of X chromosome inactivation and reactivation in mechanistic detail may uncover pathways and processes that will enhance our understanding of pathological processes associated with ageing and cancer. Naïve pluripotent stem cells are also widely used as a platform for early developmental research, with much investment being focussed on both understanding how cells maintain their naïve state and how they commit to becoming specific cell types. The proposed research will provide insights into how we might be able to stabilise stem cells in this naïve state, providing more stable stem cell platforms for use as a research tool, in drug discovery programmes and in regenerative medicine applications. Our research group has a strong track record in stem cell biology and has the necessary expertise to successfully compete this important project. Further, working within the Cambridge Stem Cell Institute puts us in a strategically strong position, with close collaborators including Professor Austin Smith, who can provide access to new stem cell lines to facilitate pioneering research.

在人类和大多数哺乳动物中，个体的性别是由一对性染色体的存在决定的：女性的XX，男性的XY。X染色体携带大约800个基因，其中包含对身体功能至关重要的遗传信息。正常、健康的基因“剂量”是通过一条染色体的存在来传递的。在携带一个X和一个Y染色体（XY）的男性中，这种遗传剂量自然传递。在携带两条X染色体（XX）的女性中，正确的遗传剂量是通过沉默其中一条X染色体获得的，这一过程被称为“X染色体失活”。自1961年发现X染色体失活以来，支持这一过程的确切机制一直是广泛研究的焦点。我的团队最近有了一个令人惊讶的发现，男性在早期胚胎发育中也会经历X染色体失活，尽管是短暂的。这一发现有可能改变对X染色体失活机制的科学理解。在本研究中，我们建议使用来自小鼠和人类的幼稚多能干细胞来研究X染色体失活。幼稚多能干细胞是代表胚胎发育最早阶段的细胞，具有精确自我复制或转变为体内任何细胞类型的能力。我们的研究将揭示这些幼稚细胞在关键胚胎发育阶段的变化如何启动男性和女性的X染色体失活。建立这些过程是我们理解早期发育干细胞生物学的核心，并将改变目前公认的X染色体失活是女性特有现象的范式。在医学方面，X连锁基因的随机重新激活已被报道在衰老和癌细胞中。了解X染色体失活和再激活的过程中的机械细节可能会发现的途径和过程，将提高我们的理解与衰老和癌症相关的病理过程。幼稚多能干细胞也被广泛用作早期发育研究的平台，大量投资集中在了解细胞如何保持幼稚状态以及它们如何致力于成为特定的细胞类型。这项拟议的研究将为我们如何能够在这种幼稚状态下稳定干细胞提供见解，为药物发现计划和再生医学应用提供更稳定的干细胞平台作为研究工具。我们的研究小组在干细胞生物学方面有着良好的记录，并拥有成功竞争这一重要项目所需的专业知识。此外，在剑桥干细胞研究所内工作使我们处于战略上的有利地位，与包括奥斯汀·史密斯教授在内的密切合作者可以提供新干细胞系的获取机会，以促进开创性研究。

项目成果

Auxin-degron system identifies immediate mechanisms of Oct4

生长素-降解决定子系统识别 Oct4 的直接机制

• DOI: 10.1101/2020.09.21.306241
• 发表时间: 2020
• 作者: Bates L

Long-Term Perfusion Culture of Monoclonal Embryonic Stem Cells in 3D Hydrogel Beads for Continuous Optical Analysis of Differentiation

• DOI: 10.1002/smll.201804576
• 发表时间: 2019-02-01
• 期刊: SMALL
• 影响因子: 13.3
• 作者: Kleine-Bruggeney, Hans;van Vliet, Liisa D.;Hollfelder, Florian
• 通讯作者: Hollfelder, Florian

StemBond hydrogels control the mechanical microenvironment for pluripotent stem cells.

• DOI: 10.1038/s41467-021-26236-5
• 发表时间: 2021-10-21
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Labouesse C;Tan BX;Agley CC;Hofer M;Winkel AK;Stirparo GG;Stuart HT;Verstreken CM;Mulas C;Mansfield W;Bertone P;Franze K;Silva JCR;Chalut KJ
• 通讯作者: Chalut KJ

Auxin-degron system identifies immediate mechanisms of OCT4.

• DOI: 10.1016/j.stemcr.2021.05.016
• 发表时间: 2021-07-13
• 期刊: Stem cell reports
• 影响因子: 5.9
• 作者: Bates LE;Alves MRP;Silva JCR
• 通讯作者: Silva JCR

StemBond hydrogels optimise the mechanical microenvironment for embryonic stem cells

StemBond 水凝胶优化胚胎干细胞的机械微环境

• DOI: 10.1101/768762
• 发表时间: 2019
• 作者: Labouesse C