Identification of chromosomal components that stabilize cell differentiation and restrict nuclear reprogramming

我们的身体由有限数量的器官组成，如大脑、心脏、胰腺等；每个器官由几十亿个细胞组成。一个器官中的细胞几乎不会转变为另一个无关器官的细胞特征。即使正常的新细胞是由它们自己的干细胞分裂产生的，它们也会成为与它们被取代的细胞相同的类型：它们记住了自己的祖先。因此，细胞的专门化状态非常稳定。然而，如果正常细胞细胞核周围的细胞质在实验中发生变化，这可能会导致该细胞核的基因活动发生戏剧性的变化。它的记忆丧失了，与新的细胞质结合在一起，它可以在体内产生各种不同的细胞。例如，这使得将皮肤细胞的核转移到一种新的细胞质中成为可能，从而产生一系列新的细胞类型，如脑、心脏等。因此，形成了与原始皮肤细胞具有相同遗传结构的新细胞，因此可以将其提供给不需要免疫抑制的个体，如果细胞在任何不相关的个体之间转移，这是一个破坏性的过程。我们问分化稳定或逆转的机制是什么？要回答这些问题，我们需要知道成年细胞核的哪些成分一方面保持其特化记忆，另一方面必须改变哪些成分才能使其恢复活力。理想情况下，我们会一个接一个地拆解成体细胞核的成分，直到它忘记了它的专门化。我们建议的关键部分是，我们已经设计了一种方法，通过这种方法可以逐步拆除细胞核。我们将细胞核移植到一种叫做两栖卵母细胞的特定细胞中，这种细胞可以提供对核的记忆(更具体地说，是表达的基因)的测试。通过这种方式，我们可以找出原子核的哪些组成部分承载着它的记忆。我们的项目会带来什么好处？首先，我们将知道细胞需要哪些成分来保持其正常、健康的功能。其次，我们将知道必须从细胞中去除哪些成分才能产生具有治疗价值的替代细胞。

Our bodies consist of a limited number of organs, such as brain, heart, pancreas etc.; each consists of a few thousand million cells. Hardly ever does a cell in one organ switch to become a cell characteristic of another unrelated organ. Even when normal new cells are produced by division of their own stem cells, they become the same kind of cell as those that they replace: they remember their ancestry. Therefore the specialized state of a cell is extraordinarily stable. However, if the cytoplasm that surrounds the nucleus of a normal cell is changed experimentally, this can cause a dramatic switch of the gene activity of that nucleus. Its memory is lost, and in combination with its new cytoplasm, it can generate every different kind of cell in the body. This makes it possible, for example, to transfer the nucleus of a skin cell to a new kind of cytoplasm, and so generate a whole range of new cell-types, such as brain, heart, etc. Therefore new cells of the same genetic constitution as the original skin cell are formed and can therefore be given to an individual who does not need to be immunosuppressed, a damaging procedure if cells are transferred between any unrelated individuals. We ask what is the mechanism of the stability or reversal of differentiation?To answer these questions, we need to know what are the components of an adult cell nucleus that, on the one hand, maintains its memory of specialization, and, on the other hand, that have to be changed to enable it to be rejuvenated. Ideally we would dismantle, one by one, the components of an adult cell nucleus until it has forgotten its specialization. The key part of our proposal is that we have devised a means by which this step by step dismantling of a cell nucleus can be done. We transplant nuclei into a particular cell, called the amphibian oocyte, which uniquely can provide a test of the memory (more specifically, the genes expressed) of a nucleus. By this way we can find out which components of a nucleus carry its memory.What benefit would result from our project? First we would know what components are needed for a cell to retain its normal, healthy function. Second, we would know what components must be taken away from cells for them to produce replacement cells of therapeutic value.