Re-defining the paradigm of X-chromosome inactivation

在人类和大多数哺乳动物中，个体的性别由一对性染色体的存在决定：雌性为XX，雄性为XY。X染色体携带大约800个基因，其中包含人体发挥功能所必需的遗传信息。正常的、健康的基因“剂量”是通过一条染色体传递的。对于携带一条X染色体和一条Y染色体(XY)的男性来说，这种遗传剂量是自然传递的。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染色体来获得的，这一过程被称为X染色体失活。自从1961年发现X染色体失活以来，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人们对X染色体失活原理的科学理解。在目前的研究中，我们建议使用来自小鼠和人类的天真多能干细胞来研究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，具有准确自我复制或在体内转变为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。在医学背景下，据报道，在衰老和癌细胞中，X连锁基因随机重新激活。了解X染色体失活和再激活的机制细节可能会揭示一些途径和过程，这将增强我们对与衰老和癌症相关的病理过程的理解。朴素多能干细胞也被广泛用作早期发育研究的平台，许多投资都集中在了解细胞如何保持其幼稚状态以及它们如何致力于成为特定类型的细胞。这项拟议的研究将为我们如何能够稳定处于这种幼稚状态的干细胞提供洞察力，提供更稳定的干细胞平台，作为研究工具，用于药物发现计划和再生医学应用。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的工作使我们处于战略上的强势地位，包括奥斯汀·史密斯教授在内的密切合作者可以提供获得新干细胞系的途径，以促进开创性研究。

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.