The genomes of all living things have been colonized by parasitic genetic elements known as transposons. If left unchecked, these have the potential to produce a significant and accumulating load of mutations at each generation. Moreover, the activity of even a single transposon can cause sterility and germ cell loss in some model systems. This creates tremendous evolutionary pressure to evolve mechanisms to discriminate transposons from endogenous genes and to selectively silence the former. During the last grant period, we uncovered a small RNA-based immune system, comprising of Piwi proteins and piRNAs, that guards germ cell genomes against the activity of genomic parasites. This system contains both genetically encoded resistance (piRNA clusters) and an adaptive component (the ping-pong cycle) that focuses responses toward active elements. In this application, we propose to deepen our understanding of the composition of the piRNA pathway, to elucidate how it discriminates self (endogenous genes) from non-self (transposons), and to probe the mechanisms by which it heritably and selectively silences selfish DNA. Though proposed studies focus on Drosophila, the mechanisms, which we study, are conserved throughout metazoans.
The goal of this application is to further understand the biological impacts of small RNAs. Small RNAs are gene regulators that impact disease states ranging from cancer to neurodegeneration. They serve as tools for understanding normal and aberrant biological processes and will perhaps transform clinical practice by serving as the basis for a new generation of therapeutic agents.
| Sanchez, Carlos G; Teixeira, Felipe Karam; Czech, Benjamin et al. (2016) Regulation of Ribosome Biogenesis and Protein Synthesis Controls Germline Stem Cell Differentiation. Cell Stem Cell 18:276-90 |
| Goh, Wee Siong Sho; Falciatori, Ilaria; Tam, Oliver H et al. (2015) piRNA-directed cleavage of meiotic transcripts regulates spermatogenesis. Genes Dev 29:1032-44 |
| Zhou, Xin; Battistoni, Giorgia; El Demerdash, Osama et al. (2015) Dual functions of Macpiwi1 in transposon silencing and stem cell maintenance in the flatworm Macrostomum lignano. RNA 21:1885-97 |
| Wasik, Kaja A; Tam, Oliver H; Knott, Simon R et al. (2015) RNF17 blocks promiscuous activity of PIWI proteins in mouse testes. Genes Dev 29:1403-15 |
| Teixeira, Felipe K; Sanchez, Carlos G; Hurd, Thomas R et al. (2015) ATP synthase promotes germ cell differentiation independent of oxidative phosphorylation. Nat Cell Biol 17:689-96 |
| Wagenblast, Elvin; Soto, Mar; Gutiérrez-Ángel, Sara et al. (2015) A model of breast cancer heterogeneity reveals vascular mimicry as a driver of metastasis. Nature 520:358-62 |
| Rechavi, Oded; Houri-Ze'evi, Leah; Anava, Sarit et al. (2014) Starvation-induced transgenerational inheritance of small RNAs in C. elegans. Cell 158:277-287 |
| Knott, Simon R V; Maceli, Ashley; Erard, Nicolas et al. (2014) A computational algorithm to predict shRNA potency. Mol Cell 56:796-807 |
| Meikar, Oliver; Vagin, Vasily V; Chalmel, Frédéric et al. (2014) An atlas of chromatoid body components. RNA 20:483-95 |
| Goh, Wee-Siong Sho; Seah, Jun Wen Eugene; Harrison, Emily J et al. (2014) A genome-wide RNAi screen identifies factors required for distinct stages of C. elegans piRNA biogenesis. Genes Dev 28:797-807 |
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