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Epigenetic Barriers to Cell Fate Reprogramming

细胞命运重编程的表观遗传障碍

基本信息

批准号：
MR/P000479/1
负责人：
John Gurdon
金额：
$ 71.23万
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：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FP000479%2F1
关键词：
Epigenetic Barriers Cell Fate Reprogramming

项目摘要

During embryonic development, cells become increasingly committed to a certain cell fate. They rarely, if ever, change to another type. For example, as skin cell do not naturally change to, or give rise to a brain cell. However, this stable commitment of a cell can be reverted by certain experimental procedures, as for example when the nucleus of a specialised cell is transplanted to an enucleated egg. During this reprogramming, the gene expression pattern of the differentiated cell can be changed to that of an embryonic cell. This process is of interest because identifying how reprogramming takes place can help us to understand how cells maintain their identity. This is important because many pathological conditions arise from loss of cell identity. Second, the embryonic stem cells that can be obtained by reprogramming a specialised cell of one kind, e.g. a skin cell, can then be made to produce healthy specialized cells of an other kind, e.g. brain cells. This has potential application in cell-replacement therapy, where these cells can compensate the loss of irreversibly damaged or defective cells. It might be possible to derive replacement heart, neuronal or pancreatic cells from another cell type of the same individual, thereby avoiding the need for immunosuppression treatments.Despite its enormous potential, the usefulness of this approach is limited by its low efficiency, as only a small number of cells can be reprogrammed. The reason why adult body cells like skin do not respond to nuclear reprogramming is likely related to an inherent resistance of one kind of cell to change to another kind. Indeed, cells produced by transplanting the nucleus of a specialised cell to an egg often continue to show characteristics, such as expression of genes, of the specialised cell they were derived from. For example, a reprogrammed skin cell continues to express skin genes and fails to fully activate genes of the new cell type. This suggests that during specialisation, cells have acquired memory of their cellular identity, which prevents unwanted changes in cell type during normal development or during reprogramming.The aim of our project is to elucidate the phenomenon of cellular memory. We use nuclear transplantation of specialised cell nuclei to Xenopus eggs as a model system to understand this process. In stark contrast to human eggs, Xenopus eggs are readily available in large quantities and easy to manipulate. Since the mechanisms underlying cellular memory are most likely conserved between vertebrates, and given the ethical concerns of using human material for this kind of research, Xenopus is the ideal model system to perform this study. The project consists of three stages. First we will investigate how many embryos produced by nuclear transfer show a strong memory of the cell type they were derived from. We will identify the genes that show cellular memory after nuclear transplantation. Second, we will investigate the molecules associated with cellular memory genes, since these molecules likely inhibit a change in cell fate during normal development and during nuclear reprogramming. Lastly, we propose to change the memory-conferring factors in specialised cells before transplanting their nuclei to eggs in order to increase the efficiency of new cell type generation. In this way, we will understand which modifications of nuclei can improve the generation of high quality embryonic cells that can be used for cell replacement. Furthermore, we will gain a better insight into the mechanisms important for cellular memory and the stability of cell differentiation during normal development and disease.

在胚胎发育过程中，细胞越来越倾向于某种细胞命运。他们很少，如果有的话，改变成另一种类型。例如，皮肤细胞不会自然地变成或产生脑细胞。然而，细胞的这种稳定定型可以通过某些实验程序来逆转，例如当将特化细胞的细胞核移植到去核卵中时。在这种重编程过程中，分化细胞的基因表达模式可以改变为胚胎细胞的基因表达模式。这个过程很有趣，因为确定重新编程如何发生可以帮助我们了解细胞如何保持其身份。这一点很重要，因为许多病理状况是由细胞身份的丧失引起的。第二，胚胎干细胞可以通过对一种特殊细胞（例如皮肤细胞）进行重编程而获得，然后可以产生另一种健康的特殊细胞，例如脑细胞。这在细胞替代疗法中具有潜在的应用，其中这些细胞可以补偿不可逆损伤或缺陷细胞的损失。从同一个体的另一种细胞类型中获得替代的心脏、神经元或胰腺细胞是可能的，从而避免了免疫抑制治疗的需要。尽管这种方法具有巨大的潜力，但由于只有少量细胞可以被重新编程，因此其有效性受到其低效率的限制。皮肤等成年体细胞对核重编程没有反应的原因可能与一种细胞对改变为另一种细胞的固有抵抗力有关。事实上，通过将特化细胞的细胞核移植到卵子中产生的细胞通常会继续显示出它们所来源的特化细胞的特征，例如基因表达。例如，重新编程的皮肤细胞继续表达皮肤基因，并且不能完全激活新细胞类型的基因。这表明在特化过程中，细胞已经获得了对其细胞身份的记忆，这可以防止在正常发育或重编程过程中细胞类型发生不必要的变化。我们使用专门的细胞核移植到非洲爪蟾卵作为模型系统，以了解这一过程。与人类卵形成鲜明对比的是，非洲爪蟾卵很容易大量获得，并且易于操作。由于细胞记忆的基本机制很可能在脊椎动物之间保存，并且考虑到使用人类材料进行此类研究的伦理问题，非洲爪蟾是进行这项研究的理想模型系统。该项目包括三个阶段。首先，我们将研究有多少通过核移植产生的胚胎显示出对它们所来源的细胞类型的强烈记忆。我们将确定核移植后显示细胞记忆的基因。其次，我们将研究与细胞记忆基因相关的分子，因为这些分子可能抑制细胞在正常发育和核重编程过程中的命运变化。最后，我们建议在将细胞核移植到卵子之前改变特化细胞中的记忆赋予因子，以提高新细胞类型产生的效率。通过这种方式，我们将了解细胞核的哪些修饰可以提高可用于细胞替代的高质量胚胎细胞的生成。此外，我们将更好地了解细胞记忆和正常发育和疾病期间细胞分化稳定性的重要机制。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

H3K4 Methylation-Dependent Memory of Somatic Cell Identity Inhibits Reprogramming and Development of Nuclear Transfer Embryos.

DOI：
10.1016/j.stem.2017.03.003
发表时间：
2017-07-06
期刊：
Cell stem cell
影响因子：
23.9
作者：
Hörmanseder E;Simeone A;Allen GE;Bradshaw CR;Figlmüller M;Gurdon J;Jullien J
通讯作者：
Jullien J

Fluid mechanics of mosaic ciliated tissues

镶嵌纤毛组织的流体力学