Small non-coding RNAs play remarkable roles in regulating gene expression by binding to Argonaute family proteins and guiding them to recognize their targets. We are interested in understanding how small RNAs function as a surveillance system that defends the genome against foreign nucleic acids, such as transposons. A conserved subfamily of Argonaute, named PIWI, binds PIWI-interacting RNA (piRNA) and plays critical roles in silencing transposons in various animals. Using C. elegans as a model organism, our recent study suggests PIWI and >25,000 genome-encoded piRNAs survey the whole transcriptome to detect "non-self" nucleic acids. Interestingly, our research demonstrated that piRNAs can establish "non-self memory" that silences its targets over multiple generations! In addition, self-transcripts appear to be protected by another group of small RNAs from piRNA silencing.

Genetic analyses have laid the groundwork for our knowledge of this defense system, but the molecular mechanisms are still poorly understood. We aim to investigate several fundamental questions including: 1. How do piRNAs recognize their RNA targets/ 2. How are "self" and "non-self" memories established and inherited? 3. How are various small RNAs produced and specifically associated with distinct Argonaute complexes? By applying complementary approaches including genomics, genetics and biochemistry, we aim to identify important principles of small RNA-based genome defense mechanisms that are likely conserved between different animals. Importantly, as PIWI mutants exhibit fertility defects in various animals, we hope our research will provide important insights toward the molecular pathogenesis of infertility.