January 14, 2019

All living organisms are at risk of invasion of foreign nucleic acids, including viruses and genomic parasites known as transposons. Failure to defend the invasion of these foreign nucleic acids can lead to various illnesses and diseases, including infertility and cancer. However, RNA molecules can act as weapons and help defend cells from foreign molecules. Heng-Chi Lee, assistant professor of molecular genetics and cell biology at the University of Chicago, leads a research team studying the tiny RNA molecules known as Piwi-interacting RNAs (piRNAs), which play critical roles in silencing foreign molecules.

In a paper published in Science last year, Lee and his team outlined how piRNAs have diverse genetic sequences and are able to identify foreign molecules to stop them from spreading. 

“We basically solved the Rosetta Stone of how the piRNA recognizes foreign molecules by cracking their code,” Lee said.

To solve the piRNA targeting code, Lee and his team used earthworms, which have piRNA similar to humans. The researchers added new piRNAs to the earthworms’ reproductive system cells and monitored how the cells would respond. Computational analyses were then used to identify piRNA targets and to reveal the code. The discovery of piRNA targeting code provides an important breakthrough for gene engineering: it solves the long-standing problem of gene silencing that biologists encounter when they try to express foreign sequences in earthworms. Using the newly identified code, Lee’s lab wrote a computer program that helps scientists quickly design sequence that avoids being turned off by piRNAs and therefore can be expressed in earthworms. Many laboratories throughout the world are now using the application program and gene sequence for genome engineering developed by Lee’s group.

The discovery of piRNA targeting code further allows Lee’s lab to ask the central fundamental question: how do cells distinguish themselves from foreign nucleic acids? Surprisingly, they found that many self genes from earthworms carry unique DNA sequences that protect them from being silenced by piRNAs. The lab is currently investigating how these DNA elements act to promote gene expression.

“Loss of piRNAs leads to severe fertility defects in various animals, including roundworms and mice. Therefore, our understanding of such genome defense mechanism potentially help us uncover some defects in humans who have infertility problems,” Lee said. “our study might also uncover a new diagnostic tool that for certain types of infertility.”