Specifically, their findings in the December 2, 2008, issue of PLoS Biology point to the three dimensional chromatin packaging around genes formed by tight, rosette-like loops of Polycomb group proteins (PcG). The chromatin packaging, a complex combination of DNA and proteins that compress DNA to fit inside cells, provides a repressive hub that keeps genes in a low expression state.

"We think the polycomb proteins combine with abnormal DNA methylation of genes to deactivate tumor suppressor genes and lock cancer cells in a primitive state," says Stephen B. Baylin, M.D., Virginia and D.K. Ludwig Professor of Oncology and senior author.

Prior to this discovery, investigators studying cancer genes, looked at gene silencing as a linear process across the DNA, as if genes were flat, one dimensional objects. Research did not take into account the way genes are packaged.

To better understand the role of the PcG packaging, the team compared embryonic cells to adult colon cancer cells. The gene studied in the embryonic cells was packaged by PcG proteins, in a low expression state, and had no DNA methylation. When the gene received signals for cells to mature, the PcG loops were disrupted and the gene was highly expressed. However, when the same gene was abnormally DNA methylated, as is the case in adult, mature colon cancer cells, the PcG packaging loops were tighter and there was no gene expression. "These tight loops touch and interact with many gene sites folding it into a structure that shuts off tumor suppressor genes," says Baylin. However, when the researchers removed DNA methylation from the cancer cells, the loops loosened somewhat, back to the state of an embryonic cell, and some gene expression was restored.

DNA methylation is a normal cellular process, but when it goes awry and genes are improperly methylated, it can shut down important tumor suppressing cell functions.

Demethylating agents, drugs that target and remove abnormal DNA methylation from genes, have been introduced as potential new cancer therapies. For these therapies to be fully effective, Baylin says, researchers may also need to look for agents that disrupt PcG loops.

hopkinsmedicine/

"Why do organisms have reactions they don't use? Presumably so they have the flexibility to adapt to different conditions. One optimization situation will engage a certain set of reactions, while another situation will require a different set. It remains to be demonstrated, however, whether different conditions alone can justify the presence of all available reactions. The fact that this question is yet to be answered makes the entire problem even more attractive," Motter said.

Motter and his team used computational results to re-interpret and explain specific recent experimental results. First they gathered extensive experimental information on the metabolic networks of four different single-celled organisms: three bacteria ( H. pylori , S. aureus and E. coli ) and yeast ( S. cerevisiae ). Then the researchers built general quantitative models of the organisms that allowed them to predict cellular behavior. With those models, the researchers conducted mathematical analyses and computer experiments, simulating the organism and its metabolic function under optimal and non-optimal conditions.

They observed that for all four organisms in a typical non-optimal state, all utilizable reactions in the metabolic network, with a few exceptions, were active. In contrast, when the four organisms were growing at their optimal rate, each of them spontaneously silenced a large number of metabolic reactions. The number of active reactions, around 300, was the same for all four, despite differences in the size and complexity of each organism's genome and metabolic network. And the number stayed around 300 for a variety of quite different optimization scenarios.

"Mathematical abstraction of the problem suggests that spontaneous shutdown may not be limited to metabolic networks," said Nishikawa, who led the mathematical part of the effort. "What appears to be essential for this phenomenon is that a complex network that is under constraints and locally in balance is 'trying' to optimize its function. There are other important systems, like transportation networks, where the same type of analyses could be useful."

northwestern/