Monya Baker
A new zinc finger protein, perhaps the first of many, silences integrated viruses
When induced pluripotent stem cells were first made, keen-eyed researchers rejoiced that the viruses required to reprogram the cells did not need to stay active indefinitely. As the cells reprogram, the viruses are silenced. That opened the door to reprogramming cells without genetic engineering, which meant that the resultant cells would be more applicable to drug screening and cell therapies.
Though the fact that embryonic cells can silence viruses quickly has been known for decades, how they do so has been a mystery. Recently published research in Nature shows that embryonic stem (ES) cells have their own mechanisms to fend off viruses that get integrated into the genome. To figure out what these mechanisms might be, Daniel Wolf and Stephen Goff of Columbia University in New York modified DNA in a retroviral primer binding site (PBS) so that it could permanently capture protein that bound to it. (The modified DNA formed covalent cross-links to the protein when exposed to ultraviolet light.) This process identified a protein that not only bound to the PBS but also bound to another protein, called TRIM28, that Goff had previously identified as essential to silencing retroviruses that insert in the genome.
Tests of the possible candidates revealed that the bound protein was ZFP809, a member of the class of zinc finger proteins that interact with DNA. A long series of experiments involving tweaks to ZFP809, PBS, TRIM28 and the cell types being studied all confirmed that ZFP809 helps recruit TRIM28 to retroviral PBSs within the genome for subsequent silencing. In fact, expressing ZFB809 in differentiated cells rendered them more able to silence integrated retroviruses1.
"It explains why retroviruses become silenced in ES and iPS cells," explains Konrad Hochedlinger, who studies induced pluripotent stem (iPS) cells at the Harvard Stem Cell Institute in Cambridge, Massachusetts. "This group has shown before that TRIM28 is the repressor complex responsible for silencing, but the actual protein that binds to the viral DNA was not known."
It makes sense that ES cells would have additional, robust mechanisms to protect their genomes, says Goff, because these are the cells that will go on to form all other tissues. Any successful infection would result in heritable modifications being passed on to the rest of the body's cells, as well as to sperm and eggs. In fact, he suspects ZFP809 is just the tip of the iceberg. "ZPF809 is likely a hallmark of ES and iPS and other primitive cells," he says. "We know binding activities for other primer binding sites exist, and so we suspect other related zinc finger proteins might someday be found to silence other viruses, such as HIV-1."