BioWorld International Correspondent

LONDON - The discovery of a new family of enzymes that can reverse a cell's ability to switch off many of its genes could have sweeping implications for understanding the control of gene transcription.

It might be possible to develop new cancer therapies that inhibit the newly identified enzymes. The finding also could herald treatments that would force differentiated cells to re-enter earlier stages of development, perhaps even allowing them to become embryonic stem cells again.

Kristian Helin, director of the Biotech Research and Innovation Centre in Copenhagen, Denmark, told BioWorld International: "Our discovery rewrites biology. Perhaps development is not as predestined as we thought. What we have found is a new way in which cells regulate transcription, and this will turn out to be very important for our understanding of development, and of human cancer."

The work is published in the May 28, 2006, issue of Nature in a paper titled "The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3."

Helin and his colleagues were studying the ways in which cells alter their destiny by controlling the transcription of their genes. Cells that differentiate into skin cells, for example, have a particular pattern of gene expression, which is "inherited" when those cells divide. All cells have the same DNA, so mechanisms that control gene expression - called epigenetics - are responsible for cellular differentiation.

One factor that is closely linked to the pattern of gene expression is the way in which the DNA is packed into the nucleus of the cell. Cells commonly are only 10 micrometers in diameter, while the DNA is about 2 meters long. Proteins called histones play a role in tightly wrapping the DNA, compacting it in order to fit it into the nucleus. The pattern of compaction also helps to determine which genes are accessible for transcription.

The histone molecule has "tails," which the cell can modify in a variety of ways. The tails can have added phosphate groups, methyl groups, acetyl groups or ubiquitin groups, for example. Many different enzymes play roles in adding such groups and in removing them. The modifications are called epigenetic marks.

Helin said, "Such marks are believed to control the entire process of development, and the differentiation that happens during development."

Earlier research by other groups had shown that one important type of epigenetic mark is the positioning of methyl groups on lysine residues in the histone protein. The lysine residues can have one, two or three methyl groups.

Recent studies had identified enzymes that could remove single methyl groups or pairs of methyl groups from such lysine residues. But no one had managed to find an enzyme that could remove three methyl groups, leaving researchers to conclude that lysines with three methyl groups could not be modified.

"Sites with trimethylated lysine residues, known as H3K9, have been studied a lot, because they are required for the genomic stability of the cell, and for the formation of heterochromatin - a special formulation of chromatin that is transcriptionally inert," Helin said.

As reported in the Nature paper, Helin's group now has discovered a group of enzymes that can demethylate a trimethylated epigenetic mark. "This gives you a plasticity that you did not have before," Helin explained. "Now you can start reverting development."

Interestingly, one of the enzymes in this group, called GASC1, already was known to be a gene that is amplified in squamous-cell carcinoma. Helin's group also showed that levels of that enzyme are raised in prostate cancer cells.

In a further experiment, the team demonstrated that when they inhibited expression of GASC1 in cancer cells, the cells stopped growing. "This means that these proteins are essential for cell proliferation," Helin said.

The group already identified some small-molecule drugs that can inhibit the activity of the enzymes, including GASC1. "This could be the first step toward the development of new, alternative therapies for cancer," Helin said.

Helin and his colleagues now have three main aims. They want to gain a better understanding of the role of GASC1 and related enzymes in human cancer. They are going to develop mice lacking functional copies of GASC1, in the hope of finding out more about the role of that enzyme in development. Finally, they are screening small molecules to find further inhibitors of GASC1.