New insight into reprogramming of cell fate

Cell fate is governed not only by the genome, but also by chemical changes to DNA and its associated proteins, a research field called epigenetics. Modifying DNA by methylation for example, alters the DNA structure but not its sequence. These 'epigenetic' tags are one of the ways that genes get switched on or off in different places at different times, enabling different tissues and organs to arise from a single fertilised egg. When epigenetic processes go awry, diseases may occur. Epigenetics is therefore emerging as an important research area with relevance to understanding many adult conditions like heart disease, diabetes, obesity, cancer and autoimmune disorders.

Professor Wolf Reik, Associate Director at the Babraham Institute and Professor of Epigenetics at the University of Cambridge who led the research said, "With numerous human, animal and plant genomes now sequenced a key question is how genomes are regulated in normal development, health and disease. Altered regulation of the epigenome is likely to underlie many human diseases so unlocking the principles of reprogramming can be harnessed to benefit regenerative medicine and stem cell therapy."

This research at Babraham, an institute of the Biotechnology and Biological Sciences Research Council (BBSRC), reveals that AID plays an intriguing role in erasing the chemical marks that appear on the genome as an embryo develops and determine what a cell's identity will be. AID appears to be involved in removing the epigenetic tags from DNA by a process called demethylation, which has long been known to be a critical component of cellular reprogramming. A study published recently in Nature from Helen Blau's lab in Stanford backs up the findings that AID is important for reprogramming.

While it has been known that epigenetic modifications to the genome get erased and re-established in the early embryo, precisely how and the extent to which this occurs had remained elusive. This collaboration between scientists at Babraham, the Howard Hughes Medical Institute and University of California at Los Angeles (UCLA) reveals for the first time the massive extent to which erasure of epigenetic tags occurs in mammals, erasing the epigenome between generations.

They discovered that methylation levels drop from 80% to a staggering 7% before being re-established again. This defines the level of epigenetic inheritance of DNA methylation patterns between generations and is identifying parts of the genome apparently more resistant to reprogramming than others. Reik explained, "Whole epigenomes can now be unravelled and understood thanks to Next Generation Sequencing technology which we used in collaboration with the UCLA team, and which we also have at the Babraham, a partner in the East Anglia Sequencing and Informatics Hub."

The Aid gene is normally switched on early as the embryo develops, however, the Babraham team found that if the AID protein is missing in cells, the methylation patterns are not thoroughly wiped clean and an epigenetic 'memory' is inherited. Commenting on the discovery Reik said, "Clear mechanisms for DNA demethylation have been elusive for some time. The body of evidence is now pointing to indirect demethylation through the action of key enzymes such as AID."

Environmental factors can also affect the genome, producing epigenetic changes that influence cell behaviour. Reik added, "It is now well established that epigenetics is the 'integrator' between the environment and the genome and that external factors like nutritional signals may have consequences later in life or on future generations. There is also the possibility that epigenetic information could be inherited across generations, providing a shorter term and flexible type of inheritance in response to environmental signals. The ability to unravel whole epigenomes during normal development and healthy ageing, and to understand how epigenomes are modified by the environment is extremely exciting."

It is known that removing epigenetic information from the genome can induce adult cells to regain stem-cell like properties (induced pluripotent stem cells, iPS cells). Inducing 'pluripotency' is of direct relevance to regenerative medicine as it enables specific cell populations and tissues to be generated from and for patients. Currently reprogramming is inefficient because of the memory imparted by DNA methylation tags. These new findings pinpointing how DNA demethylation can be driven, may overcome a significant barrier in producing iPS cells.

The identification of proteins like AID, that drive epigenetic signalling, is an important advance in basic biomedical research, which may help define new targets and therapeutics for diseases including cancer. The Babraham team are pursuing commercial applications in collaboration with the company CellCentric.

"Epigenetics is a growing area of academic research and commercial development. By understanding what proteins cause cell fate change, new tools and methods can be designed for both regenerative medicine and the treatment of intractable diseases. Specifically, the identification of AID and its activity may offer the ability to test the importance of gene-specifc demethylation, as well as the potential to overcome a pivotal epigenetic barrier in reprogramming cells for induced pluripotent cell production," explained Dr Will West, CEO of CellCentric.