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.
Zhang D, Tu S, Stubna M, Wu WS, Huang WC, Weng Z, Lee HC. 2018 "The piRNA targeting rules and the resistance to piRNA silencing in endogenous genes", Science 359, 587-592. (Science)
Lee HC*, Gu W*, Shirayama M, Youngman E, Conte DJ, Mello CC. 2012 "C. elegans piRNAs piRNA medicate the genome-wide surveillance of germline transcripts", Cell. Jul 6; 150 (1): 78-87. (PubMed)
Shirayama M, Seth M, Lee HC, Gu W, Ishidate T, Conte D, Mello CC. 2012 "piRNAs initiate an epigenetic memory of non-self RNA in the C. elegans germline", Cell. Jul 6 ;150 (1): 65-77. (PubMed)
Gu W, Lee HC, Chaves D, Youngman E, Pazour GJ, Conte DJ, Mello CC. 2012 "C. elegans piRNA are processed from capped-small RNAs transcribed from promoter throughout the genome". Cell. 151(7):1488-500. (PubMed)
Lee HC*, Aalto AP*, Yang Q, Chang CC, Huang G, Fisher D, Cha J, Poranen MM, Bamford DH and Liu Y. 2010 "The DNA/RNA-dependent RNA polymerase QDE-1 generates aberrant RNA and dsRNA for RNAi in a process requiring Replication Protein A and a DNA helicase", PLOS Biol. Oct 5;8(10). pii: e1000496. (PubMed)
Lee HC*, Li L*, Gu W, Xue Z, Crosthwaite SK, Pertsemlidis A, Lewis ZA, Freitag M, Selker EU, Mello CC, and Liu Y. 2010 "Diverse pathway generates microRNA-like RNAs and Dicer-independent small interfering RNAs in fungi", Mol Cell. 38 (6): 803-814. (Cover) (PubMed)
Lee HC, Chang SS, Choudhary S, Aalto AP, Maiti M, Bamford DH, and Liu Y. 2009. "qiRNA is a new type of small interfering RNA induced by DNA damage", Nature. 459 (14):274-278. (Cover) (PubMed)
Choudhary S*, Lee HC*, Maiti M*, He Q, Cheng P, Liu Q, and Liu Y. 2007. "A double-stranded RNA response program important for RNA interference efficiency", Mol Cell Biol. 27(11):3995-4005. (Cover) (PubMed)
Maiti M, Lee HC and Liu Y. 2007. "QIP, a putative exonuclease, interacts with the Neurospora Argonaute protein and facilitates conversion of duplex siRNA into single strands", Genes & Dev. 21(5):590-600. (PubMed)
* These authors contributed equally to the study.