William E. Theurkauf, PhD, professor of molecular medicine, and Zhiping Weng, PhD, director of the Program in Bioinformatics and Integrative Biology, have uncovered a mechanism that may explain how destabilizing genetic elements related to viruses, called transposons, are turned off while other parts of the genome are allowed to function normally.
Most of the genes needed for normal cell function and development are interrupted by introns, and these interruptions have to be removed from the RNA copy of the gene by a process called splicing, before a normal protein can be produced. A study published in Cell by the Theurkauf and Weng labs details the discovery of a complex of proteins that blocks splicing of RNAs, leading to the production of Piwi-interacting RNAs (piRNAs) which silence parasitic transposons.
“Until now, it’s been unclear how the cell selects some RNAs for production of piRNAs, while others make proteins,” said Dr. Theurkauf, professor of molecular medicine at UMass Medical School. “This study suggests that differences in splicing efficiency differentiate a gene that needs to be expressed from a transposon that needs to be silenced.”
Transposons, also called “jumping genes” because of their ability to move around the genome, pose a significant threat to the genetic integrity and stability of an organism. Considered the equivalent of genetic pathogens, these small, mobile sequences of DNA are related to RNA viruses and can insert themselves into new locations in the genome, leading to mutations and disease. The piRNA pathway, which is related to RNA interference, functions as an adaptive defense system responsible for identifying and silencing these genome pathogens. How piRNAs turned off transposons while allowing protein-coding gene expression, however, was a mystery.
“Transposons have to move to survive,” said Theurkauf. “If they move, you end up with mutations that can be passed down to the next generation. If they jump into a tumor suppressing gene, for example, that can result in cancer. piRNAs are necessary to keep transposons off so that a parent’s intact genome can be transmitted to the next generation. The trick is that they have to disable the pathogen without turning off the host genes.”
Protein-coding regions of genes in complex animals are generally interrupted by short, non-coding sequences called introns. These introns are removed during a process called splicing. The same process reassembles the remaining pieces into a mature messengerRNA that is used to produce a functional protein or other needed cellular material.
Theurkauf and Weng have discovered a complex of proteins that specifically block splicing of piRNA precursors. The unspliced, intron containing, transcripts are then made into piRNAs that silence corresponding sequences in the genome, including transposons.
“These unspliced transcripts are not normal. So the cell makes a piRNA that can silence them,” said Weng. “By blocking the RNA splicing mechanisms, these protein complexes allow the genome to recognize its own genes from potential genetic pathogens that need to be silenced.”
The next step for Theurkauf and colleagues is to determine if this system, observed in Drosophila, is conserved in other animals.
“Transposons are essentially left over viruses that have been inserted into the genome,” said Theurkauf. “If we can figure out how the piRNA system works to silence transposons, it’s possible we could turn on the same system in a cell infected with a pathogenic virus, as an anti-viral therapy.”