Team Maps Epigenome of Human Stem Cells During Development

By Mika Ono

Scientists at The Scripps Research Institute and The Genome Institute of Singapore (GIS) led an international effort to build a map that shows in detail how the human genome is modified during embryonic development. This detailed mapping is a significant move towards the success of targeted differentiation of stem cells into specific organs, which is a crucial consideration for stem cell therapy.

The study was published in the genomics journal Genome Research on February 4, 2010.

"The cells in our bodies have the same DNA sequence," said Scripps Research Professor Jeanne Loring, who is a senior author of the paper with Chia-Lin Wei of the Genome Institute of Singapore and the National University of Singapore and Isidore Rigoutsos of IBM Thomas J. Watson Research Center. "Epigenetics is the process that determines what parts of the genome are active in different cell types, making a nerve cell, for example, different from a muscle cell."

Wei, who is senior group leader at the GIS, a biomedical research institute of the Agency for Science, Technology, and Research (A*STAR), said, "In this study, we mapped a major component of the epigenome, DNA methylation, for the entire sequence of human DNA, and went further by comparing three types of cells that represented three stages of human development: human embryonic stem cells, human embryonic stem cells that were differentiated into skin-like cells, and cells derived from skin. With these comprehensive DNA methylome maps, scientists now have a blueprint of key epigenetic signatures associated with differentiation."

DNA methylation causes specific subunits of DNA to be chemically modified, which controls which areas of the genome are active and which ones are dormant. DNA methylation is critical to the process in which embryonic cells change from "pluripotent stem cells," which have the ability to turn into hundreds of cell types, to "differentiated cells," distinct types of cells that make up different parts of the body, such as the skin, hair, nerves, etc.

In reviewing the data produced by the study—information on the methylation of three billion base pairs of DNA—the scientists were able to identify previously unknown patterns of DNA methylation. They identified cases where DNA methylation appeared to enhance, rather than repress, the activity of the surrounding DNA, and found evidence to suggest a role for DNA methylation in the regulation of mRNA splicing.

"We produced a very large amount of data," said Loring, "but it actually simplifies the picture. We identified patterns of many genes that are methylated or de-methylated during differentiation. This will allow us to better understand the exquisitely choreographed changes that cells undergo as they develop into different cell types."

Louise Laurent of Scripps Research and the University of California, San Diego, one of the first authors of the study, added, "The data are publicly available, and we are looking forward to learning what other scientists discover from using this information for their own studies on individual genes, embryonic development, and stem cells."

Eleanor Wong, from the Genome Institute of Singapore, is also first author of the study, "Dynamic Changes in the Human Methylome During Differentiation." In addition to Laurent, Wong, Loring, Rigoutsos, and Wei, authors of the study are Guoliang Li, Thing Ong, and Hwee Meng Low of the Genome Institute of Singapore, Tien Huynh and Aristotelis Tsirigos of the IBM Thomas J. Watson Research Center, and Chin Ken Wing Kin Sung of the Genome Institute of Singapore and the National University of Singapore. http://genome.cshlp.org/content/early/2010/02/02/gr.101907.109.abstract

Funding for this work was provided by grants from the National Institutes of Health, the California Institute for Regenerative Medicine, A*STAR of Singapore, and The Esther B. O'Keeffe Foundation.

Send comments to: mikaono[at]scripps.edu

"This will allow us to better understand the exquisitely choreographed changes that cells undergo as they develop into different cell types."

— Jeanne Loring