Vitamins A and C aren’t just good for your health, they affect your DNA too. Researchers at the Babraham Institute and their international collaborators have discovered how vitamins A and C act to modify the epigenetic ‘memory’ held by cells; insight which is significant for regenerative medicine and our ability to reprogramme cells from one identity to another. The research is published today in Proceedings of the National Academy of Science (PNAS).
For regenerative medicine, the holy grail is to be able to generate a cell that can be directed to become any other cell, such as brain cells, heart cells and lung cells. Cells with this ability are present in the early embryo (embryonic stem cells, ESC) and give rise to the many different cell types in the body. For the purposes of regenerative medicine, we need to be able to force adult cells from a patient to regress back to possessing embryonic-like capabilities and to ‘forget’ their previous identity.
A cell’s identity is established at the DNA level by epigenetic changes to the DNA. These changes don’t alter the order of the DNA letters but control which parts of the genome can be read and accessed. Consequently, every different cell type has a unique epigenetic fingerprint, enforcing and maintaining specific patterns of gene expression appropriate to the cell type. To reverse cells back to the naïve pluripotent state this epigenetic layer of information has to be lost to open up the full genome again.
Researchers from the Babraham Institute, UK, University of Stuttgart, Germany and University of Otago, New Zealand worked together to uncover how vitamins A and C affect the erasure of epigenetic marks from the genome. They looked in particular at the epigenetic modification where a methyl chemical tag is added to the C letters in the DNA sequence. Embryonic stem cells show low levels of this C tagging, called cytosine methylation, but in established cell types much more of the genome is marked by this modification. Removing the methyl tags from the DNA, called demethylation, is a central part of achieving pluripotency and wiping epigenetic memory.
The family of enzymes responsible for active removal of the methyl tags are called TET. The researchers looked at the molecular signals that control TET activity to understand more about how the activity of the TET enzymes can be manipulated during cellular programming to achieve pluripotency.
They found that vitamin A enhances epigenetic memory erasure in naïve ESC by increasing the amount of TET enzymes in the cell, meaning greater removal of methyl tags from the C letters of the DNA sequence. In contrast, they found that vitamin C boosted the activity of the TET enzymes by regenerating a co-factor required for effective action.
Dr Ferdinand von Meyenn, postdoctoral researcher at the Babraham Institute and co-first author on the paper, explained: “Both vitamins A and C act individually to promote demethylation, enhancing the erasure of epigenetic memory required for cell reprogramming.” Dr Tim Hore, previously a Human Frontier Long Term Research Fellow at the Babraham Institute, now Lecturer at the University of Otago, New Zealand and co-first author on the paper, continued: “We found out that the mechanisms of how vitamins A and C enhance demethylation are different, yet synergistic.”
The improved understanding of the effect of vitamin A on the TET2 enzyme also potentially explains why a proportion of patients with acute promyelocytic leukaemia (once considered the deadliest form of acute leukaemia) are resistant to effective combination treatment with vitamin A. By providing a possible explanation for this insensitivity for further investigation, this work could point the way to better management of the vitamin A resistant cases.
Professor Wolf Reik, Head of the Epigenetics Programme at the Babraham Institute, said: “This research provides an important understanding in order to progress the development of cell treatments for regenerative medicine. It also enhances our understanding of how intrinsic and extrinsic signals shape the epigenome; knowledge that could provide valuable insight into human disease, such as acute promyelocytic leukaemia and other cancers. Putting the full picture together will allow us to understand the full complexity of the epigenetic control of the genome.”
A University of Otago botany researcher and colleagues have developed a new system to map the world’s “biomes”— large-scale vegetation formations — that will provide an objective method for monitoring how vegetation reacts as climate changes.
The system uses satellite observations of the timing and intensity of vegetation activity and how this relates to temperature and soil moisture to classify the world’s vegetation into 24 biome types.
Several other global biome maps exist, but the researchers’ goal was to produce one that is not reliant on expert opinion or correlations between vegetation and climate.
Botany Professor Steven Higgins says they used their new classification scheme to examine change in biomes over time and found that 13 per cent of the Earth’s land surface changed its biome state over the last three decades.
“This suggests that substantial shifts in the character of the Earth’s surface are under way. Examples include swathes of Nambia and north-central Australia transitioning into drier biome categories and large expanses of cold limited systems shifting to more productive categories.”
Professor Higgins says while global change is the likely driver of the biome shifts detected, their study did not attempt establish such causal links.
“Future studies could use this system to monitor biome change and attribute the causes of the change.
“Our system provides an objective way to classify the land surface, which is important not only for monitoring change but also for comparing the behaviour of ecosystems in different parts of the world. These comparisons are essential for understanding the drivers of ecosystem dynamics and how ecosystems might respond to change.
“If such comparisons are underpinned by a faulty biome classification we end up comparing apples with oranges.”
The University of Otago (Māori: ‘Te Whare Wānanga o Otāgo’) in Dunedin is New Zealand’s oldest university.
It had over 21,000 students enrolled during 2011.
The university has New Zealand’s highest average research quality and in New Zealand is second only to the University of Auckland in the number of A rated academic researchers it employs. It topped the New Zealand Performance Based Research Fund evaluation in 2006.
Founded in 1869 by a committee including Thomas Burns, the university opened in July 1871. Its motto is “Sapere aude” (“Dare to be wise”). (The University of New Zealand subsequently adopted the same motto.) The Otago University Students’ Association answers this with its own motto, “Audeamus” (“let us dare”). The university’s graduation song Gaudeamus igitur, iuvenes dum sumus… (“Let us rejoice, while we are young”) acknowledges students will continue to live up to the challenge if not always in the way intended. Between 1874 and 1961 the University of Otago was a part of the University of New Zealand, and issued degrees in its name.