BioWorld Today Correspondent

LONDON - The arrangement of genes in the nuclei of cells is highly organized to an "exquisite" degree, scientists have found. All the genes involved in the specific function of a particular type of cell cluster together in transcription "factories" in the nucleus, where the cell coordinates production of all the proteins it needs.

Explaining some of the mysteries of how cancer is caused, the finding suggested that chromosomal translocations - where chromosomes break and exchange their DNA - may occur because genes present at the break point meet in the transcription factories.

One day, this work could lead to the development of a "virtual nucleus," a tool that would allow scientists to simulate interactions in the nucleus, and which could revolutionize computer-based drug design.

Peter Fraser, head of the Laboratory of Chromatin and Gene Expression at the Babraham Institute in Cambridge, UK, told BioWorld Today: "Our findings indicate that the nucleus is far more organized than anyone thought. Just 10 or 15 years ago, people had the idea that the nucleus was like a plate of spaghetti with all the different chromosomes totally disorganized. Around 2000, researchers developed the concept of chromosome territories. But we have now found that there is exquisite organization of genes in the nucleus, with transcription factories and silencing compartments and so on."

Fraser and his colleagues carried out a genomewide scan of the genes being transcribed in one type of cell, using an assay that allowed them to detect interactions between chromosomes and a sophisticated three-dimensional fluorescent imaging technique.

They could see that certain genes on separate chromosomes would colocalize with each other at high frequencies when transcription was taking place.

"If you consider the volume of the nucleus, the chances of any two genes coming together - especially if they are on different chromosomes - is about one in 1,500," Fraser said. "But we saw certain pairs of genes that colocalized on about 25 percent of occasions, which seemed to prefer to be together when they were transcribing."

The team had already observed that this was true for the immunoglobulin heavy chain locus in B cells, which colocalized with the myc proto-oncogene, when the latter was switched on. "This was an interesting observation because about 80 percent of patients with Burkitt's lymphoma - a type of B cell lymphoma - have translocations between Myc and the immunoglobulin heavy chain locus," Fraser said.

For the latest study, published in the Dec. 13, 2009, issue of Nature Genetics, Fraser and his collaborators decided to use their method to examine the transcription of the globin genes in murine erythroid cells. In their paper, titled "Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells," they described how genes encoding proteins with a related physiological role visit the same transcription factory. The work was funded by the Medical Research Council and the Biotechnology and Biological Sciences Research Council.

"What we detected," Fraser said, "was genes involved in the entire physiological pathway of iron uptake, iron transport, the incorporation of iron into heme, and the incorporation of heme into the alpha and beta globin peptides to make hemoglobin."

The most surprising finding, he added, was that a single transcription factor, called Klf1, was responsible for the colocalization of all the different genes involved. "When we knocked out this transcription factor from mice, and repeated the experiment using their cells, we could see that the nuclear organization of these genes was completely disrupted. This suggests that the genes in normal cells really are sharing a type of factory."

All the gene products involved in the manufacture of hemoglobin were affected, from the transferrin receptor that pulls iron into the cell, the iron transport protein that pulls iron into the mitochondria (where heme synthesis takes place), about eight different enzymes involved in heme biosynthesis, the globin proteins, a hemoglobin chaperone protein that helps in the assembly of hemoglobin, to proteins involved in setting up a scaffold for hemoglobin on the inner surface of the red cell membrane. Even an ion transport protein that controls intracellular pH by pumping biocarbonate ions in and out of the cell - thereby influencing hemoglobin's affinity for oxygen - was present in the same transcription factory.

Fraser said: "All of the genes encoding these enzymes will need to be switched on simultaneously in erythroid cells, and at just the right levels - an excess of heme or of globin can be toxic. We think that this is some sort of adaptation to allow cells to control the coordinated output of this tissue-specific pathway of genes."

Every type of tissue will have some groups of genes that operate in a similar manner, he added, whether muscle cells, nerve cells, liver cells and so on.

In ongoing studies, Cameron Osborne, a group leader at the Babraham, is investigating the impact of genome organization on people's susceptibility to cancers like leukemia. "A key aim will be to see whether other genes involved in translocations associated with specific cancers are preferentially found together at transcription factories," Osborne said. "If so, this could represent a common and fundamental step in cancer development. Ultimately, these studies will have wide-ranging implications in human health and disease and may point the way to novel forms of treatment for cancer patients."