The Hidden Code of Stem Cells

The DNA of embryonic stem cells is labeled in a unique and characteristic way, according to new research from scientists in California. The pattern could shed light on how embryonic stem cells maintain their ability to become any type of cell and might also help efforts to clone these cells, allowing scientists to develop better stem cell therapies.

Embryonic stem cells have the ability to become virtually any cell in the body, making them the basis for potential therapies to treat everything from Parkinson’s disease to diabetes. But before these cells can be developed into useful therapies, scientists must better understand the genetic root of the cells’ unique properties – and learn to control them.

“It’s very likely that these [labels] point to regions of the genome that are crucial for maintaining the self-renewing capacity of embryonic stem cells,” says James Battey, chair of the Stem Cell Task Force at the National Institutes of Health in Bethesda, MD.

Epigenetic changes to DNA are those that alter expression of certain genes, for instance by reversibly tagging those genes, without changing the sequence of the DNA itself. In a paper published last week in Genome Research, researchers studied one such process, called DNA methylation, in which certain molecules within the gene are chemically modified, altering the activity of that particular gene.

Scientists have previously been able to study DNA methylation in a single or a few genes. But in the new study, researchers developed a technology to look at methylation patterns in hundreds of genes at a time.

Jian-Bing Fan, research director at Illumina, a gene analysis company based in San Diego, CA, modified the company’s gene microarrays – tiny chips labeled with specific sequences of DNA – so that they could simultaneously detect DNA methylation at 1,500 sites in the genome.

Researchers then analyzed 14 lines of embryonic stem cells, as well as adult cells and cancer cells. They found that the embryonic stem cells had a unique methylation pattern, regardless of where the cells came from or how they were generated. That pattern was significantly different from patterns found in adult stem cells, adult differentiated cells, and cancer cell lines.

“All our collaborators at 11 institutions across the world were surprised to see such a unique signature, given that all lines come from people of different ethnic origins and were isolated and grown under different conditions,” says Fan.

The findings could help stem cell scientists in numerous ways. For example, one concern associated with stem cell-based therapies is that they could form tumors when injected into the body – embryonic stem cells share some qualities of cancer cells, notably, their ability to divide indefinitely. But the findings show that the two cells types are actually very different.

“In cancer cells, the methylation pattern seems very unstable, whereas it was very stable in embryonic stem cells and adult stem cells,” says Jeanne Loring, a scientist at the Burnham Institute in San Diego, CA, who led the work. She adds that in the future, when scientists have developed different therapies derived from embryonic stem cells, DNA methylation screening could be used to assess cells’ potential to become cancerous once transplanted.

The findings could also shed light on the unique ability of embryonic stem cells to become any type of cell. Now that scientists know what the baseline pattern is, they can study how that pattern changes when cells begin to differentiate into nerve cells, heart cells, or other cell types. “We can turn stem cells into these cells in culture and ask what happens to their epigenetic profile,” says Loring. “We are poised to understand that for first time.”

“This could be the start of some very interesting experiments,” adds Ihor Lemischka, a biologist at Princeton University who studies stem cells. “It would be interesting to ask: What is the nature of the genes that are differentially regulated?”

The technology might also shed light on the tricky process of human cloning. To attempt to create cloned stem cells, scientists take the nuclei from an adult cell and transfer it to an egg with its nucleus removed. Some unknown factors in the egg “reprogram” the genome of the adult nucleus, reverting the DNA to its embryonic state and allowing the fertilized egg to develop as a normal embryo would.

Stem cells derived from these embryos could be used for personalized cell therapies or to study complex genetic diseases (see “Stem Cells Reborn”). While this process has been carried out successfully in mice and other animals, no one has yet achieved the feat with human cells. “This work and some that came before indicates that the epigenetic pattern of embryonic stem cells is very precise,” says Loring. “You’re not just asking the adult nucleus to erase everything, you’re asking it to erase everything and then reformat in a very specific way.”

Scientists want to better understand the reprogramming process so they can eventually reprogram adult cells without eggs – human eggs are a very limited resource and using them for research is ethically questionable to many people. The new findings could help scientists see exactly what they need to achieve when designing new reprogramming technologies. Says Loring: “if we know what the pattern is, we can try to get that pattern with other methods.”