Fairfax, VA, USA. An international scientific effort has built a detailed map that shows how the human genome is modified during embryonic development. Billions of data points were analyzed to provide a big picture of the human epigenome during a critical developmental window. This is a significant move towards the targeted differentiation of stem cells into specific organs, a crucial consideration for stem cell therapy.

Scientists at The Genome Institute of Singapore (GIS) and The Scripps Research Institute (TSRI) led an international team and published their findings in the journal Genome Research.

Chia-Lin Wei, Ph.D., is the senior author and Senior Group Leader at the GIS, a biomedical research institute of Singapore's Agency for Science, Technology and Research (A*STAR). Wei reports that "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." The three types were human embryonic stem cells, human embryonic stem cells that were differentiated into skin-like cells, and cells derived from skin.

"Scientists can now survey different cell types and developmental pathways, identify the genes affected, and characterize the functions of these genes in the process of differentiation."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 (e.g., skin, hair, nerves).

With these comprehensive DNA methylome maps, scientists now have a blueprint of key epigenetic signatures associated with differentiation. "The cells in our bodies have the same DNA sequence," said TSRI Professor Jeanne Loring, Ph.D., who is a co-senior author of the paper along with Isidore Rigoutsos of IBM and Chia-Lin Wei.

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 in which 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 TSRI 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."

"This is definitely an exciting finding in the field of stem cell research," added co-first author Eleanor Wong, who is a graduate student from the GIS in Dr Wei's lab. "Using this knowledge, scientists can now survey different cell types and developmental pathways, identify the genes affected, and characterize the functions of these genes in the process of differentiation. It's all very exciting!"

CitationDynamic changes in the human methylome during differentiation. Louise Laurent, Eleanor Wong, Guoliang Li, Tien Huynh, Aristotelis Tsirigos, Chin Thing Ong, Hwee Meng Low, Ken Wing Kin Sung, Isidore Rigoutsos, Jeanne Loring, and Chia-Lin Wei. Genome Research 2010; ePub ahead of print. doi:10.1101/gr.101907.109

Abstract

DNA methylation is a critical epigenetic regulator in mammalian development. Here, we present a whole-genome comparative view of DNA methylation using bisulfite sequencing of three cultured cell types representing progressive stages of differentiation: human embryonic stem cells (hESCs), a fibroblastic differentiated derivative of the hESCs, and neonatal fibroblasts. As a reference, we compared our maps with a methylome map of a fully differentiated adult cell type, mature peripheral blood mononuclear cells (monocytes). We observed many notable common and cell-type-specific features among all cell types. Promoter hypomethylation (both CG and CA) and higher levels of gene body methylation were positively correlated with transcription in all cell types. Exons were more highly methylated than introns, and sharp transitions of methylation occurred at exon–intron boundaries, suggesting a role for differential methylation in transcript splicing. Developmental stage was reflected in both the level of global methylation and extent of non-CpG methylation, with hESC highest, fibroblasts intermediate, and monocytes lowest. Differentiation-associated differential methylation profiles were observed for developmentally regulated genes, including the HOX clusters, other homeobox transcription factors, and pluripotence-associated genes such as POU5F1, TCF3, and KLF4. Our results highlight the value of high-resolution methylation maps, in conjunction with other systems-level analyses, for investigation of previously undetectable developmental regulatory mechanisms.

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