The differentiated state of adult cells is remarkably stable, and ensures the normal function of our body tissues and organs. Hardly ever does a cell of one kind change into a different kind of cell. However, there are certain experimental procedures by which gene expression of a specialised adult cell can be reversed to that of an embryonic cell. This opens the way to provide therapeutically useful replacement cells of any kind from other readily available cells of another kind, such as skin.

One procedure for reversing the differentiated state of a cell is by transplanting its nucleus to an egg or oocyte. Our aim is to understand how eggs or oocytes achieve this, so as to identify the reprogramming molecules involved, and thus, eventually, to improve the efficiency of this route towards cell replacement without immunosuppression.

We use the growing eggs (“oocytes”) of amphibia to activate embryo-expressing genes in the transplanted nuclei of adult mammalian cells. We have recently identified polymerised actin and its cofactors as a significant component of this oocyte transcriptional apparatus for reprogramming somatic nuclei. A question of at least as much importance is how the differentiated state of a cell makes its nucleus resistant to the reprogramming activities of an oocyte. Genes that become transcriptionally repressed in normal development are of this kind. Such genes show an epigenetic memory of their quiescent state. We have identified macroH2A as one chromatin protein that helps to confer an inactive state of genes on the inactive X chromosome of female mammals. We have recently developed a procedure by which chromosomal proteins can be progressively removed from somatic cell nuclei to improve embryonic gene reactivation. This can lead to the identification of chromosomal components that resist reprogramming by oocytes. The removal of these could greatly improve the efficiency of nuclear reprogramming.
Selected publications:

A model of changes in chromatin state during reprogramming.

A dramatic difference exists in the ability of an oocyte to active Scleraxis (Scs) or Thy 1 genes in different cell types.

Plain English:
We are trying to find ways of obtaining embryo cells from the cells of an adult. The eventual aim is to provide replacement cells of all kinds starting from usually obtainable cells of an adult individual. For example, we would like to be able to find a way of obtaining spare heart or brain cells from skin or blood cells. The important point is that the replacement cells need to be from the same individual, to avoid problems of rejection and hence of the need for immunosuppression. We are trying to identify the molecules and mechanisms by which eggs can reverse the process of specialization, so as to derive embryo cells from adult skin cells.

Selected publications:

• Miyamoto K, Pasque V, Jullien J and Gurdon JB (2011) Nuclear actin polymerization is required for transcriptional reprogramming of Oct4 by oocytes. Genes & Development 25(9):946-958

• Pasque V, Gillich A, Garrett N and Gurdon JB (2011) Histone variant macroH2A confers resistance to nuclear reprogramming. EMBO J 6;30(12):2373-87

• Jullien J, Halley-Stott RP, Miyamoto K, Pasque V and Gurdon JB (2011) Mechanisms of nuclear reprogramming by eggs and oocytes: a deterministic process? Nature Reviews Molecular & Cell Biology, 12, 453-459

• Narbonne P, Simpson DE and Gurdon JB (2011) Deficient induction response in a Xenopus nucleocytoplasmic hybrid. PLoS Biology 9(11):e101197

• Pasque V, Jullien J, Miyamoto K, Halley-Stott RP and Gurdon JB (2011) Genetic and epigenetic factors affecting nuclear reprogramming efficiency. Trends in Genetics 27(12)516-525

Polymerised nuclear actin enhances nuclear repogramming.

Transcription of an inactive X chromosome of mice is inhibited in part by manoH2A.