Vitamins A and C help erase 'memory' in stem cells

Vitamins A and C can enhance success in the challenging process of converting adult cells into stem cells, an international study co-led by a University of Otago researcher has found.

The research team discovered that the two vitamins complement each other in erasing "memory" associated with DNA, an important effect for improving technologies geared towards regenerative medicine and stem cell therapy.

The findings are published this week in Proceedings of the National Academy of Science (PNAS).

Ordinary adult cells, such as those in the skin or blood, can be artificially coerced in a culture dish to resemble embryos only a few days old.

Study co-lead author Dr Tim Hore of Otago’s Department of Anatomy says that since the 2006 discovery that this remarkable reprogramming process is possible, there has been much interest in using induced embryonic stem cells to cure human disease.

"However, hampering these efforts is the reality that adult cells are resistant to changes in their identity, partly because of chemical alterations to their DNA," Dr Hore says.

He says that these alterations, known as "DNA methylation", are acquired during development and provide a form of cellular memory that helps cells faithfully maintain a specialised function. Removal of this memory is critical in order to create a developmentally potent stem cell, or to change one kind of adult cell to another.

Dr Hore was previously a Human Frontier Long Term Fellow at the UK’s Babraham Institute. Along with collaborators at Babraham and in Stuttgart, Germany, he determined that adding vitamins A and C to culture dishes synergistically removes DNA methylation from embryonic stem cells.

When applied to cells during the reprogramming process, those with the desired "naïve" embryonic characteristics were created in much greater numbers, he says.

The mechanism by which this occurs was also detailed in the study.
"We found that both vitamins affect the same family of enzymes which actively remove DNA methylation; it turns out that Vitamin A increases the number of these enzymes within the cell, and Vitamin C enhances their activity," he says.

In addition to regenerative medicine, this work may have implications for other areas of biomedical importance. Loss of DNA methylation and cellular memory are a hallmark of certain cancers, so a better understanding of how this process occurs could prove significant.

"Along with other Otago research groups, my lab is beginning to explore how the vitamin-induced effects we have uncovered in this study might impact on the loss of DNA methylation in certain cancers," he says.

This work was funded by the Wellcome Trust, the Biotechnology and Biological Sciences Research Council, the Medical Research Council, the European Union EpiGeneSys Network of Excellence, the European Union BLUEPRINT Consortium (awarded to senior author, Professor Wolf Reik), the Human Frontier Science Program (Dr Tim Hore), the Swiss National Science Foundation/Novartis (Dr Ferdinand von Meyenn) and the German Research Foundation (Associate Professor Tomasz Jurkowski).

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Simple blood test may spot 5 types of cancers

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Higher amounts of DNA methylation (hypermethylation), like that found by researchers in some tumour DNA, decreases a gene's activity. 

A simple blood test may be used to diagnose five types of cancers - colon, lung, breast, stomach and womb - at early stages, scientists say. Researchers from National Institute of Health (NIH) in US have identified a striking signature in tumour DNA that occurs in these types of cancers. They also found evidence that this methylation signature may be present in many more types of cancer. The specific signature results from a chemical modification of DNA called methylation, which can control the expression of genes like a dimmer on a light switch.

Higher amounts of DNA methylation (hypermethylation), like that found by researchers in some tumour DNA, decreases a gene's activity. Based on this advance, researchers hope to spur development of a blood test that can be used to diagnose a variety of cancers at early stages, when treatments can be most effective. "Finding a distinctive methylation-based signature is like looking for a spruce tree in a pine forest. It is a technical challenge to identify, but we found an elevated methylation signature around the gene known as ZNF154 that is unique to tumours," said Laura Elnitski from NIH.

For the study, researchers developed a series of steps that uncovered telltale methylation marks in colon, lung, breast, stomach and endometrial cancers. They showed that all the tumour types and subtypes consistently produced the same methylation mark around ZNF154. "Finding the methylation signature was an incredibly arduous and valuable process. These findings could be an important step in developing a test to identify early cancers through a blood test," said Dan Kastner from NIH. Researchers sequenced the tumour DNA that had been amplified using a technique called polymerase chain reaction (PCR). They then analysed the results, finding elevated levels of methylation at ZNF154 across the different tumour types.

To verify the connection between increased methylation and cancer, they developed a computer programme that looked at the methylation marks in the DNA of people with and without cancer. By feeding this information into the programme, they were able to predict a threshold for detecting tumour DNA. Even when they reduced the amount of methylated molecules by 99 per cent, the computer could still detect the cancer-related methylation marks in the mixture.

Knowing that tumours often shed DNA into the bloodstream, researchers calculated the proportions of circulating tumour DNA that could be found in the blood, researchers said. The findings were published in The Journal of Molecular Diagnostics.