Distinct methylation in stem cell DNA

Findings may help explain why embryonic stem cells can self-renew and are pluripotent

By | August 7, 2006

The DNA of human embryonic stem cells contains patterns of methylation that are distinct from those in other cells, scientists report in the September Genome Research. These findings may shed light on what mechanisms give embryonic stem cells their unique ability to self-renewal and become different cell types. The researchers also found that methylation patterns in embryonic stem cells differed significantly from those seen in cancer cells, suggesting that some similarities between the two types of cells might simply be "coincidental," said coauthor David Barker, vice president and Chief Scientific Officer at Illumina in San Diego, which develops tools to analyze genetic data (including the microarrays used in this study). This finding may help alleviate concerns that embryonic stem cells are prone to forming tumors, the authors note. "Despite the fact that embryonic stem cells can keep growing forever like cancer cells, our findings show they are definitely not alike when it comes to methylation profiles," Barker told The Scientist. If human embryonic stem cells contain a unique epigenetic signature, therapeutic cloning likely faces enormous challenges, added coauthor Jeanne Loring from the Burnham Institute in La Jolla, Calif. "With therapeutic cloning, we want the cells after somatic cell nuclear transfer to be reborn to be just like embryonic stem cells," Loring explained. "We don't know the extent to which epigenetics may be important in that reprogramming. So we now have to learn what methylation patterns we want or have to achieve." Methylation and demethylation of DNA have profound consequences on genetic activity and cellular behavior, but little is known about what effects epigenetic changes might have on embryonic stem cells. The investigators systematically analyzed human embryonic stem and other cells, using microarrays with oligonucleotide probes that mapped methylation patterns in the cells. The researchers tested more than 1,500 potential DNA methylation sites from 371 genes in 14 human embryonic stem cells lines derived in several different labs and raised for different times in culture. Many of these genes, such as tumor suppressors, were cancer-related. The human embryonic stem cells shared essentially identical methylation patterns in 49 methylation sites from 40 genes. The patterns were easily distinguishable from those present in four somatic stem cell lines, 25 cancer lines, four normal tissue lines, and four B cell lines. "Others among the 371 [stem cell genes] were also very similar," Barker said. The researchers did report some differences in methylation patterns between the human embryonic stem cell lines, although these proved slight compared to the differences between the embryonic stem cells and other cell types. The more passages embryonic stem cells experienced, the more they appeared to differ from other cells of the same line that underwent fewer passages. No specific set of genes changed predictably between the cell lines. This work is "an interesting initial look into what might be done" to study the epigenetics of stem cells, "but it's only a start," Stephen Baylin at Johns Hopkins University in Baltimore, who did not participate in this study, told The Scientist. For instance, some genes may have "50, 100, 150" methylation sites that need to be investigated, he said. To truly understand if or how DNA methylation patterns change over time for human embryonic stem cells in culture or as they differentiate, scientists will have to study and track cells "from the very beginning" to set a baseline, Alexander Olek at Epigenomics in Berlin, also not a coauthor, told The Scientist. Future research should also investigate the functional significance of these methylation patterns using concurrent gene expression studies, Guoping Fan at the University of California, Los Angeles, also uninvolved in the research, told The Scientist. Loring noted that she and her colleagues plan to conduct experiments that examine methylation profiles in other genes, including those related to embryonic stem cell functions such as differentiation. Charles Choi cchoi@the-scientist.com Links within this article M. Bibikova et al. "Human embryonic stem cells have a unique epigenetic signature." Genome Research, September 2006. http://www.genome.org/ R. Lewis. "Stem cells... An emerging portrait," The Scientist, July 4, 2005. http://www.the-scientist.com/article/display/15592/ David Barker http://www.illumina.com/company/management/about_team.ilmn R. Pollack. "Crafting a consensus on therapeutic cloning." The Scientist, October 11, 2004. http://www.the-scientist.com/article/display/14997/ Jeanne Loring http://www.burnham.org/default.asp?contentID=241 R. Lewis. "The clone reimagined." The Scientist, April 25, 2005. http://www.the-scientist.com/2005/04/25/13/1/ L.A. Pray. "Epigenetics: Genome, meet your environment." The Scientist, July 5, 2004. http://www.the-scientist.com/article/display/14798/ J. Kling. "Put the blame on methylation." The Scientist, June 16, 2003. http://www.the-scientist.com/article/display/13873/ Stephen Baylin http://www.hopkinsmedicine.org/graduateprograms/cmm/baylin.html T Hollon, "Diagnosis cancer: A genomics and proteomics approach," The Scientist, September 22, 2003. http://www.the-scientist.com/article/display/14127/ Guoping Fan http://www.neuroscience.ucla.edu/faculty-page.asp?key=1540

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