Map of billions

Scripps Research and GIS map out epigenome of human stem cells during development

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LA JOLLA, Calif.—Astronomer Carl Sagan hosted the educational television series "Cosmos" in 1980 and is immortalized by a line that is typically misquoted and truncated as "billions and billions of stars." But while that might be incorrect and out of context, there's another science-oriented "billions and billions" that is very pertinent right now—the billions of data points that provide a "big picture of the human epigenome during critical developmental window," according to scientists at the Scripps Research Institute and the Genome Institute of Singapore (GIS).

Recently, the Scripps and GIS researchers led an international effort to build a kind of map showing in detail how the human genome is modified during embryonic development, publishing their article, "Dynamic Changes in the Human Methylome During Differentiation," online Feb. 4 in advance of the print issue of the genomics journal Genome Research. They say that this detailed mapping is a significant move toward achieving targeted differentiation of stem cells into specific organs—which is, in turn, a crucial consideration for stem cell therapy.

"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," explains Chia-Lin Wei, senior group leader at GIS, a biomedical research institute of the Agency for Science, Technology and Research (A*STAR), who is one of the paper's senior authors. "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 to differentiated cells, notes Jeanne Loring, a Scripps research professor and one of the other senior authors.

The study produced data on the methylation of three billion base pairs of DNA, allowing the team to identify previously unknown patterns of DNA methylation, including cases in which DNA methylation appeared to enhance, rather than repress, the activity of the surrounding DNA. Their findings also suggest DNA methylation plays a role in the regulation of messenger RNA (mRNA) splicing.

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

Further clarifying the need for such a large data set, Louise Laurent of Scripps Research and the University of California, San Diego, one of the first authors of the study, adds that previous to a whole-genome approach like this, researchers have had to be selective about what genes and parts of genes to study."When you have to make decisions like that about what to focus on, and what to leave out, you bias your data in a certain sense," Laurent says. "You limit yourself and make it harder to analyze the data later because you don't have a complete picture."

Laurent also notes that while the focus of the Scripps-GIS team was on stem cells, the methods that she and her colleagues used can be generalized to any kind of cell. There is, in fact, a very high interest already in using the team's methods on cancer cells, Laurent reports. Their methods also hold promise for such efforts as performing quality control on cells populations that will be used for transplantation.

"There are many things you can look at, such a biomarkers," Laurent says, "but this kind of comprehensive examination of methylation provides another important window of understanding, and is part of the orthogonal approach to studying the genome."

In addition to Wei and Loring, Isidore Rigoutsos of IBM's T.J. Watson Research Center, is a senior author, and Eleanor Wong of GIS—like Laurent—is a first author. Other authors of the study are Guoliang Li, Thing Ong, and Hwee Meng Low of GIS; Tien Huynh and Aristotelis Tsirigos of the T.J. Watson Research Center; and Chin Ken Wing Kin Sung of the GIS and the National University of Singapore. 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.

Oh, and just in case it's not just those billions of data points on DNA methylation that got your interest, and you really want to know, Sagan's actual quote was, "A galaxy is composed of gas and dust and stars—billions upon billions of stars."

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