Are geneticists ready for the circulome?
For decades biologists have known of mysterious rings of DNA in the nuclei of some human cells, interspersed among the linear chromosomes. Now, what were once curiosities are increasingly looking like key players in health and disease. The circulome, a term introduced at the Biology of Genomes meeting here, may turn out to be a new frontier in genetics. At the meeting, Massa Shoura, a biophysicist at Stanford University in Palo Alto, California, reported that she had adapted a biophysics technique to better survey human cells for so-called extrachromosomal circular DNA (eccDNA), finding diverse complements of independent loops in many kinds of cells. Other recent work suggests that by carrying multiple copies of specific genes, the rings can affect cells’ functions or boost the growth of cancers. One recent paper even proposes that by releasing such loops, cells can influence other, distant cells. This circular DNA is “going to turn out to be extremely important,” predicts Paul Mischel, a cancer biologist at the Ludwig Institute for Cancer Research at the University of California, San Diego (UCSD). Not to be confused with circular bacterial chromosomes or circular RNA— another newly recognized cellular actor (Science, 31 March, p. 1363)—these rings of DNA were first spotted in the nuclei of plant cells. Then other scientists, finding similar free-standing DNA loops in brain cancer cells, speculated that they might give tumors a genetic boost by carrying extra copies of cancer-related genes. This year, Mischel confirmed those suspicions. He and his colleagues revealed that very large DNA circles—up to 5 million base pairs—exist in half of all human cancers, but are rarely found in normal cells. “Levels can be sky high in some tumors,” Mischel says. The cancer cell rings carry many copies of the oncogenes driving the tumor growth, potentially churning out more cancerpromoting protein than chromosomebound copy alone could, he and his colleagues reported on 2 March in Nature.
When a cell divides, such DNA rings replicate as well, but—unlike chromosomal DNA—they may not be evenly apportioned between the daughter cells. They can pile up in one cell, greatly increasing the number of copies of the oncogene it contains. If the extra oncogenes give the cell a big growth boost, that cell type can take over the tumor cell population, Mischel says. The DNA rings may even transfer an oncogene back onto the cell’s linear DNA—his team has found oncogenes outside their normal chromosome locations in cells with the circular DNA. “It provides a different way of thinking about how cancers evolve,” Mischel says. Roel Verhaak, a cancer biologist at Jackson Laboratory for Genomic Medicine in Farmington, Connecticut, found similar evidence that eccDNA contributes to cancer growth. His group recently assessed gene activity in tumors from 13 glioblastoma patients and found DNA circles carrying the cancer-promoting gene MET boosted its activity in those cancer cells, as wellas in tumors that grew when the human cells were implanted in mice. (That work is unpublished but the data were posted in a preprint last year.)
The team found that the circles varied widely in size and gene content, the largest being 16,000 bases. “That they exist in normal cells with such huge complexity is amazing,” says Anindya Dutta, a molecular biologist at the University of Virginia in Charlottesville, who with his colleagues did an earlier, more limited search for eccDNA in normal and cancer cells (Science, 6 April 2012, p. 82). As Shoura described at the meeting, the circular DNA repertoire varies from cell to cell, perhaps providing a handy way to distinguish cell types, she suggested. (A recent preprint on bioRxiv also details her team’s results.) Preliminary work suggests that each cell type’s complement of circles may also help it specialize. Heart muscle cells, for example, have eccDNA with lots of genes for a particular form of the muscle protein titin. “Extrachromosomal circular DNA is one way that the genome could have some plasticity in it,” notes Kelly Frazer, a genome scientist at UCSD. “It looks like this may be happening in normal development and other types of processes.” Dutta has recently found that DNA rings may help cells communicate, even over long distances. When human tumor cells are grafted into mice, human DNA circles soon appear in the rodent circulatory system, he and his colleagues report in the 26 May issue of Molecular Cancer Research.The shed DNA may transport gene fragments to other cells, although that hasn’t been shown yet. It could also form the basis of a cancer blood test, Dutta says. He further suggests that RNA transcribed from DNA circles could fine-tune gene activity and protein production. For now, the potential roles of these DNA circles are making biologists’ heads spin. “It basically opens a new field and a new way of thinking about DNA and about how dynamic the genome is,” Shoura says.
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