Protein helps regulate the genes of embryonic stem cells

Findings offer new ideas on disease states

New research from University of North Carolina at Chapel Hill shows how a protein may be crucial to the regulation of genes in embryonic stem cells. The protein, called “eed,” is needed for an essential chemical modification of many genes. Embryos cannot survive without the modification.

The findings appear in the May 24 issue of the journal Current Biology.

The research offers an important contribution to a new wave of thinking in genetics: that not all human disease states are due to alterations in DNA sequence. Dr. Terry Magnuson – Sarah Graham Kenan professor, chairman of genetics and director of the Carolina Center for Genome Sciences in UNC’s School of Medicine – led the research.

Researchers five decades ago worked to crack the genetic code, the nucleic acid sequence of As, Cs, Gs and Ts making up the DNA of genes. Today, Magnuson’s team is trying to unravel a different, newly appreciated mode of inheritance: epigenetics.

“Epigenetic inheritance is heritable information passed down through generations of cells that is not encoded by the DNA sequence,” said Nathan D. Montgomery, a graduate student in Magnuson’s laboratory and first author of the paper.

This information is in the form of chemical modifications on any of four core histone proteins that group together to provide a molecular scaffold supporting the roughly 35,000 genes in the nucleus of every human cell. Histone modifications affect gene activity and include methylation, in which a methyl component is attached to the histone protein.

The prevailing model is that methylation on histones serves as a docking site for proteins that “read” this histone modification, and it’s those proteins that directly have an impact on gene expression – either by activating or silencing a gene.

“Diversity is determined by different types of chemical modifications and also by the number of modifications,” Montgomery said. “And those modifications are the unit of epigenetic information, just as the DNA sequence is the unit of genetic information.” Depending on the precise nature of the histone modification, any given gene associated with modified histones is marked to be turned on or off.

In the study, eed is the first protein shown to be required for the addition of a single methyl group to histone H3, said Montgomery. Knowing which proteins are responsible for the various histone modifications is the first step toward understanding how epigenetics influences such occurrences as cancer and birth defects, he added.

The discovery that eed is required to modify histone H3 in a unique way opens up new lines of investigation into the role eed might play in diverse biological processes.

“It may give us new gene targets to study relative to cancer and other disease states that may have these marks and have not been examined but should be,” Magnuson said.

Another application of epigenetics is stem cell therapeutics, in which any specific tissue type could be derived from stem cells and used to replace damaged or diseased tissue.

Magnuson and his colleagues chose to study how eed influences genes in embryonic stem cells because they thought that would be directly applicable to stem cell technologies.

“In order to get a handle on individual stem cell therapeutics and make this application work, one has to begin to understand the epigenetics of the embryonic stem cells, and we really have very little information on that kind of technology,” said Magnuson.

In addition to Magnuson and Montgomery, department of genetics authors include Della Yee, lab technician; Andrew Chen, undergraduate researcher; and Drs. Sundeep Kalantry and Stormy J. Chamberlain, postdoctoral fellows. Arie P. Otte, professor at the Swammerdam Institute for Life Sciences, Amsterdam, also contributed.