How Cells Achieve Omnipotence

In the first moments after a sperm fertilizes an egg, cytosine bases on the newly combined DNA are rapidly demethylated to create an all-powerful embryonic stem cell, but exactly how this occurs has long kept scientists guessing. Now researchers led by Guo-Liang Xu, a biochemist at the Chinese Academy of Sciences in Shanghai, have finally pinpointed enzymes that can coordinate this elusive process, known as “active demethylation” (Science, DOI: 10.1126/science.1210944).

“People have been searching for the mechanism of active demethylation for decades,” says Chuan He, a chemist at the University of Chicago and a member of the research team. The results provide the first detailed biochemical blueprint for one of biology’s most important processes, the origin of life, He says.

According to the new research, a methylated cytosine—which silences transcription of genes containing the mark—is demethylated by several enzymes. First, a family of enzymes called Tet oxidizes 5-methylcytosine to 5-hydroxymethylcytosine and then to 5-carboxylcytosine. Next, a glycosylase enzyme called TDG removes the 5-carboxylcytosine from the double-stranded DNA. Loss of the base activates DNA repair enzymes to insert a cytosine base at the same spot on the DNA. This new proposed pathway does not proceed via a deamination step, which was included in earlier models, He says.

“This research provides the most direct biochemical evidence to date of active demethylation—they’ve found enzymes capable of executing their proposed pathway,” comments Suneet Agarwal, a stem cell biologist at Harvard Medical School. However, to conclusively prove that the proposed pathway is the elusive active demethylation mechanism, he says, it must be shown to be active in a newly formed zygote, as opposed to the human kidney embryonic stem cells used in the research. This is in fact what Xu says he’s working on.