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

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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.