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Forget it—Stem cells start with clean slate

EMORY (US)—New findings about how sperm and egg unite to create new life may have implications for stem-cell therapies and cloning. Emory University scientists have pinpointed a process that erases information in fertilized eggs to create a zygote—the ultimate stem cell.

The study involving a microscopic worm commonly used for analyzing cell differentiation offers some of the first direct evidence of a process required for epigenetic reprogramming between generations.

“One of the most fundamental mysteries in biology is how a sperm and egg create a new organism. By looking at the process at the molecular level, we’re gaining understanding of this basic question of life,” says David Katz, lead author of the study and a postdoctoral fellow at Emory.

When a sperm cell fertilizes an egg cell, the specialized programming of each parent cell must be erased, in order to form a zygote that can give rise to a new organism. The process by which these two differentiated cells return to a developmental ground state in the zygote is little understood.

“We believe that we have demonstrated one of the processes that erases the information in a fertilized egg, so that the offspring can begin life with a clean slate,” says Katz.

‘An amazing phenotype’
The Emory researchers wanted to test the theory that removal of a particular histone protein modification involved in the packaging of DNA—dimethylation of histone H3 on lysine 4—is involved in reprogramming the germ line.

They compared successive generations of a normal strain of the microscopic worm C. elegans with a mutant strain. The mutants lacked an enzyme that test-tube experiments have previously shown appears to play an “erasing” role—demethylating histones to remove information from the packaging of DNA.

In the normal strain of the worms, the histone modification the Emory researchers had targeted was not passed on to the next generation, but in the mutant strain the modification continued through 30 generations, and each generation became progressively less fertile.

“That’s an amazing phenotype,” Katz says. “The organism gradually lost its ability to reproduce. We have shown that when this enzyme is missing, the worms can inherit the histone modification—not only from cell to cell, but from generation to generation.”

When the researchers reinserted the missing enzyme into the sterile generations of mutant worms, they were able to reverse the process: The worms no longer inherited the histone modification, and they regained fertility.

Inheriting an epigenetic event
For years, it’s been accepted that histone proteins help coil six-foot strands of DNA into tight balls, compact enough to fit inside the nucleus of a cell. Histone modifications have also been known to correlate with gene expression. More recently, researchers have theorized that a chemical change in the histone packaging of DNA, known as an epigenetic event, can be passed on—just as genes themselves can be inherited.

“This study is one of the first demonstrations in a living organism that this theory may be true—that every generation can be affected by an epigenetic event,” says William Kelly, associate professor of biology at Emory and a co-author of the study.

“Our work provides some of the best, direct evidence that chemical modifications in the packaging of DNA can be inherited from cell to cell,” Katz adds. “That indicates that these chemical modifications are not just involved in packaging—they contain information.”

Groundwork for stem-cell therapies
A better understanding of the role of histones, and the enzymes involved in their modification, could lead to therapies for everything from cancer to infertility. “Stem-cell therapies are an incredibly promising technology for treating any problem that has to do with defective cells,” Katz explains. “We’re hoping that our work will help this technology to develop.”

Katz and his colleagues are now building on the results of the study, to see if a lack of the erasing enzyme shows a similar effect in mice—the normal laboratory model for humans.

The research was funded by a grant from the National Institutes of Health.

Emory University news: www.emory.edu/home/news

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