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International Team Maps Methylation Changes During Cellular Differentiation

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A team of researchers from Singapore and the US has mapped and compared DNA methylation changes across the genome in human cells at three progressive stages of differentiation.

In the paper, online today in Genome Research, researchers from the Genome Institute of Singapore, the Scripps Research Institute, and elsewhere used bisulfite sequencing to discern DNA methylation patterns in differentiating human cells at three developmental stages. After comparing these with methylation maps from adult cells, the team was able to begin teasing apart shared and cell type-specific methylation patterns — providing insights into how methylation shifts during development.

"With these comprehensive DNA methylome maps, scientists now have a blueprint of key epigenetic signatures associated with differentiation," co-corresponding author Chia-Lin Wei, a researcher affiliated with the Genome Institute of Singapore and the National University of Singapore, said in a statement.

DNA methylation is one of several epigenetic processes involved in regulating gene expression and helping guide the development — and maintenance of — various cell types.

"The cells in our bodies have the same DNA sequence," co-senior author Jeanne Loring, a researcher at the Scripps Research Institute, said in a statement. "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."

For instance, the researchers explained, elevated DNA methylation frequently marks genes being silenced. And in mammalian cells, methylation often occurs at sites in the genome called CpG islands — sequence rich in neighboring cytosine and guanine nucleotides.

To get a clearer picture of DNA methylation patterns across the genome during cellular differentiation, the team used bisulfite sequencing with the Illumina Genome Analyzer to look at three human cell types, each at a slightly more differentiated state: embryonic stem cells, fibroblastic cells derived from embryonic stem cells, and primary neonatal fibroblast cells.

They verified the patterns detected with this sequencing approach by comparing the results to results generated by assessing CpG methylation at more than 27,300 sites in the same cell types using the Illumina Infinium Human Methylation27 BeadChip microarray.

When they compared the DNA methylation patterns in the three cell types to those in fully differentiated white blood cells, the researchers found that the embryonic stem cells had the highest levels of methylation overall.

As reported in past studies, much of the methylation occurred at CpG sites. But, the researchers reported, compared with the other cell types tested, embryonic stem cells had higher levels of non-CpG methylation as well.

The most common type of non-CpG methylation in these cells was CpA methylation, which diminished as cells differentiated, showing up less and less frequently in the fibroblastic and neonatal fibroblast cells. Nevertheless, they added, a sub-set of conserved CpA sites was also methylated in the more differentiated cells.

By combining methylation and transcription data, the team was also able to gain insights into how methylation affects expression at different sites in the genome. For instance, they found that, as expected, DNA methylation around a gene's transcription start sites was linked to low expression, while methylation at other sites, including transcription termination sites, corresponded to higher expression of a gene.

Their subsequent analyses offered a peek at how genome-wide methylation relates to a range of other features in the genome, from splicing to chromatin features. In addition, they also started narrowing in on regions of the genome — and specific genes — that are differentially methylated as cells become increasingly specialized. As such, those involved in the study say the findings lay the foundation for a better understanding of cellular development and regulation.

"We identified patterns of many genes that are methylated or de-methylated during differentiation," Loring said, "This will allow us to better understand the exquisitely choreographed changes that cells undergo as they develop into different cell types."

The team plans to make data from the study freely available to other researchers.

"[W]e 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," co-lead author Louise Laurent, a researcher affiliated with the Scripps Research Institute and the University of California at San Diego who is currently doing research in Loring's lab, said in a statement.

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