A discovery by Babraham scientists brings new insight into how cells are reprogrammed and a greater understanding of how the environment, or factors like nutritional signals, can interact with our genes to affect health. As an embryo develops, cells acquire a particular fate, for example becoming a nerve or skin cell. The findings, reported online in the journal Nature, pinpoint a protein called AID as being important for complete cellular reprogramming in mammals. In addition, these findings may advance the field of regenerative medicine, by potentially enhancing our ability to guide the reversal of cell fate, and pave the way for novel therapeutics.
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 laboratory 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.
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Popp C, Dean WL, Feng S, Cokus SJ, Andrews SR, Pellegrini M, Jacobsen SE, Reik W (In press)
Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency
Nidhi Bhutani, Jennifer J. Brady, Mara Damian, Alessandra Sacco, Stéphane Y. Corbel & Helen M. Blau.
Reprogramming towards pluripotency requires AID-dependent DNA demethylation
Nature, advance online
Notes to Editors:
The Babraham Institute is a charitable organisation devoted to biomedical research and is an institute of the Biotechnology and Biological Sciences Research Council (BBSRC). The Institute’s research is focused on understanding the biological events that underlie the normal functions of cells and on how their failure or abnormality may lead to disease. As such, Institute scientists are striving to find cures for conditions where there is currently no treatment or where the existing treatment is not fully effective or causes serious side effects. The latest technologies are being used to study the basis of conditions such as neurodegenerative disorders, birth defects, cancer and diseases of the immune and cardiovascular systems. With a strategic focus on ‘healthy ageing’, novel approaches for tackling chronic diseases and public health concerns like obesity are being discovered. The Institute’s innovative research is commercialised through Babraham Bioscience Technologies (BBT) Ltd, which also manages Babraham’s vibrant Bioincubator on the Babraham Research Campus, six miles south-east of Cambridge. Website: www.babraham.co.uk
The Biotechnology and Biological Sciences Research Council (BBSRC) is the UK funding agency for research in the life sciences. Sponsored by Government, BBSRC annually invests around £450 million in a wide range of research that makes a significant contribution to the quality of life for UK citizens and supports a number of important industrial stakeholders including the agriculture, food, chemical and pharmaceutical sectors. BBSRC carries out its mission by funding internationally competitive research, providing training in the biosciences, fostering opportunities for knowledge transfer and innovation and promoting interaction with the public and other stakeholders on issues of scientific interest in universities, centres and institutes.
The Babraham Institute, Institute for Animal Health, Institute of Food Research, John Innes Centre and Rothamsted Research are Institutes of BBSRC. The Institutes conduct long-term, mission-oriented research using specialist facilities. They have strong interactions with industry, Government departments and other end-users of their research.
Epigenetic mechanisms are at the heart of developmental biology, orchestrating the formation of many different tissues and organs from a fertilised egg. Almost all cells in an individual have exactly the same genetic material, yet behave very differently depending on which organs they comprise. It is 25 years since scientists first suspected that there might be heritable biological information separate from the DNA sequence – another inheritance ‘code’. Epigenetic regulation enables the fine tuning of our genes and their expression in different places at different times, leading to the amazing complexity we see in humans despite the relatively small number of unique genes.
We all get two copies of every gene, one from our mother and one from our father. In many cases both copies are used or ‘expressed’, however it is becoming clear that for some genes either the mother’s or the father’s version is used preferentially, a phenomenon known as genomic imprinting. Specific chemical modifications to the DNA, such as methylation, appear to give the chromosomes a "memory" as to their parental origin. These ‘epigenetic’ imprints, from the Greek meaning ‘on top of’, modify the structure of the DNA but not its sequence. In addition to parental modifications, it is thought that epigenetic changes may also arise in response to environmental factors, enabling an organism's genes to adapt and respond differently, even though the gene sequence does not change.
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