The keys to the transdifferentiation
The role of various factors can be described as the different layers in an onion. While TF are at the heart of the mechanism providing control and basal efficiency of the process, the EF involved act as additive protective layers, which insulate the process against variations induced by the environment.
Aug. 15, 2014
Will we soon be able to replace our aging or injured tissues? Can we envision new approaches in regenerative medicine through the efficient reprogramming of the cell identity? During organogenesis, cells acquire and maintain specialized characteristics until their death. An uncontrolled loss of these features can result in cancer. However, a particularly rare and interesting phenomenon has been discovered recently: some cells do lose their identity to acquire a new one. This mechanism called "transdifferentiation" thrills scientists, with its many potential applications in regenerative medicine... The team of Sophie Jarriault has just unravelled the key factors that determine the efficiency and robustness of this conversion mechanism in the worm C. elegans. These results are published on August 15th 2014 in the journal Science.
Transdifferentiation in question
Our body is made of millions of cells, each with a specific function within our organs: these are coined ‘differentiated’ cells and they maintain their specialised, differentiated identity until their death. However, recent discoveries have shown that in some cases this differentiated identity was not fixed. Indeed it has been shown that some cells may change their fate and acquire new features, a rare phenomenon called "transdifferentiation". Sophie Jarriault’s team studied this process in a simple organism, C. elegans. A few millimeters in length, this little worm is particularly easy to study as it is transparent and has a limited and fixed number of cells. These amenities have made it possible for the first time to precisely follow the fate of a cell and observe in real time the natural transdifferentiation of a rectal cell into a moto-neuron, an essential step in the normal development this worm.
Within the stability of the process
After having shown that transdifferentiation in C. elegans takes place with invariant precision in time and space and involves a dedifferentiation step, the researchers got interested in the factors responsible for this invariance. To do this, they conducted a genetic screen, isolating all mutants in which transdifferentiation was altered in one way or another. They have been able to uncover the role of several transcription factors, which are proteins involved upstream of genes to regulate their expression. But they also discovered the importance of 'epigenetic' factors, i.e. molecules capable of modulating gene expression by acting on the structures around which DNA is wrapped: the histones. Whether during the dedifferentiation phase, or during the subsequent redifferentiation step, the researchers showed the importance of the dynamic aspect of the mechanism, allowing the sequential activity of all these molecules.
In most processes, the respective importance and function of genetic versus epigenetic factors remain unclear. This work suggests a model where transcription factors act to drive transdifferentiation with a strong basal efficiency, while epigenetic factors ensure the remarkable complete efficiency of the phenomenon under "normal" conditions. In addition, epigenetic factors have an essential role to ensure the robustness of the process in unfavourable or stressful environemental conditions. "Like the layers of an onion, we have realized that transcription factors are at the heart of process, while epigenetic factors form the outer layers that insulate the mechanism against variations induced by environmental changes" says Sophie Jarriault.
Although still poorly understood, natural transdifferentiation events have been observed in many different species including vertebrates and in a wide range of tissues (eye, enteric nervous system, lungs, pancreas, etc.), and are often associated with regeneration after injury. The results obtained by Sophie Jarriault’s team provide new keys to better understand the mechanisms controlling the process and its efficiency, which could lead to promising therapies, especially in the field of regenerative medicine.