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CpG methylation in embryonic stems cells turns genes on

Any molecular genetics textbook will tell you that DNA methylation (the addition of a methyl group or molecule) is an epigenetic switch that turns off genes. Studies by researchers at the USDA/ARS Children’s Nutrition Research Center at Baylor College of Medicine and Texas Children’s Hospital show, however, that after human embryonic stem cells start to differentiate into different cell types and tissues, certain genome regions called CpG islands become methylated, turning on important genes involved in development.

"The methylation does not occur at the promoter region (the beginning of the gene), but at the other end called the 3’ (3 prime) region," said Dr. Lanlan Shen, associate professor of pediatrics - nutrition at BCM and corresponding author of the report in the journal Molecular and Cellular Biology.

"This study is the first to document a specific mechanism for how DNA methylation at 3’ CpG islands activates expression of associated genes," said Shen. Not only that, but using a computer algorithm to analyze large sets of DNA methylation data, she and her colleagues showed that as stem cells differentiate and become more specialized tissues and cells, these 3’ CpG islands become more and more methylated.

This methylation regulates the activation of gene transcription (the first step in translating DNA into a blueprint that eventually becomes a protein) via a mechanism that depends on the blocking of a gene enhancer by a protein called CTCF.

"The bottom line of the report is that CTCF-mediated enhancer blocking activity appears to be used by our cells as a general mechanism for regulation of gene expression during differentiation," said Dr. Robert Waterland, associate professor of pediatrics - nutrition at BCM and a member of the faculty of the Children’s Nutrition Research Center, as is Shen.

The finding is particularly important for shedding light on the complex roles of DNA methylation during mammalian development, and should lead to refinement of the ‘textbook’ view of this epigenetic modification.

Others who took part in this work include Da-Hai Yu, Miao-Hsueh Chen, Govindarajan Kunde-Ramamoorthy, Lagina M. Nosavanh and Manasi Gadkari, all of BCM, Carol Ware of the University of Washington in Seattle and Jiexin Zhang of The University of Texas MD Anderson Cancer Center.

Funding for this work came from the Sidney Kimmel Foundation, the U.S. Department of Agriculture (CRIS 624 6250-5100-050) the National Institute of General Medical Services (P01GM081619-01), the National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK081557) and private funding from the Institute for Stem Cell and Regenerative Medicine.

For more information on basic science research at Baylor College of Medicine, please go to www.bcm.edu/fromthelab.