Department of Molecular Biology, Massachusetts General Hospital
Hans-Hermann Schoene Distinguished Investigator
microRNA and RNA interference mechanisms, neuroendocrine control of detoxification, immunity, metabolism, aging, and microbial diversity
Research in the Ruvkun lab has explored three major themes: microRNA genes and other small RNAs, control of longevity and immune surveillance, and detection of life on other planets. We discovered in collaboration with Victor Ambros in 1992 that the first microRNA, lin-4, regulates the translation of a target gene, lin-14, to which it base pairs with the loops and bulges that are common in folded RNAs. The Ruvkun lab identified the second microRNA in 2000, let-7, which also regulates translation of its target gene via imperfect base pairing, and showed that the sequence and regulation of the let-7 microRNA is conserved across animal phylogeny including humans. Thousands of miRNAs across eukaryotic phylogeny were subsequently discovered by dozens of laboratories. The miRNA field has grown from the two back-to-back papers by Ambros and Ruvkun in 1993 to more than 100,000 references in 2021. The anatomy of the pairing of the lin-4 miRNA to the lin-14 mRNA and the let-7 miRNA pairing to the lin-41 target mRNA, with the bulges and loops in those duplexes are still the paradigm from which the thousands of newly discovered miRNAs and their targets are viewed. miRNAs are now used in the clinic to type tumors. miRNAs are now implicated in heart disease, in viral pathogenesis, in regulation of neural function and disease, in the transition from totipotent stem cells to differentiated cells. In plants, miRNAs mediate a variety of developmental and physiological transitions and turn out to have been key players in the domestication of corn. Human therapies based on microRNA regulation are already in clinical trials for heart disease. We also discovered many of the genes that collaborate with microRNAs and siRNAs and other small RNAs. In addition to revealing fundamental regulatory axes in biology, some of these components may be developed as drug targets to enhance RNAi in animals and plants.
The Ruvkun lab discovered that an insulin-like signaling pathway controls C. elegans metabolism and longevity. Genetic analysis in mouse and humans have validated the generality of insulin-regulation of aging. We used full genome RNAi libraries to explore the complete set of genes that regulate aging. Many of the lifespan-increasing gene inactivations target conserved genes that are also targeted by microbial antibiotics. Translation of mRNA and the mitochondrial electron transport chain are key targets of microbial toxins, and we are intensively studying the defense responses to such perceived attacks. Surveillance for these microbial attacks is coupled to detoxification and immune responses as well as endocrine axes of fertility and aging. We discovered that a wide range of bacterial species have evolved pathways to disrupt the eukaryotic surveillance of bacteria. These bacterial pathways can be dissected using a combination of genetic analysis of the bacteria and the animal host.
The engine of the Ruvkun lab has been genetic analysis, genome analysis, and functional genomics. We were early users of full genome RNAi libraries for surrogate genetics; this has been displaced in the lab over the past five years by full genome sequencing of newly generated mutations in large-scale genetic screening. In this era of full genome sequences, genetic screening has become literally 50x more productive. Recent Ruvkun lab students and postdocs have discovered entire genetic pathways in this manner. A decade ago, it was common for a single student to figure out one gene during a PhD or postdoc. We no longer endure a year of linkage mapping and chromosome walking. This is a sea change: in a period of weeks after the screen, we now identify lesions in dozens of different genes. And notice also that our genetic pathway discovery papers of 2016 to 2021 are two to three author papers; these are not hundred author Big Science papers. Genetics constantly enlarges our interests to generate new projects and perspectives. There are always many different projects, kinds of questions and approaches in the lab, which provides excellent training, intellectual flexibility and confidence. Instead of a lab where students and the PI divide increasingly smaller slices of the same pie, students and postdocs generate their own projects which they take with them to their own labs.
Soukas, AA, CE Carr, and G Ruvkun. 2013. Genetic Regulation of C. elegans Lysosome Related Organelle Function. PloS Genetics, Oct;9(10):e1003908.
Fischer, SEJ, Q Pan, PC. Breen, Y Qi, Z Shi, C Zhang, TA Montgomery, and G Ruvkun. 2013. Multiple C. elegans silencing pathways converge to silence duplicated sequences Genes and Development, 2013 Dec 15;27(24):2678-95.
Garcia, SMDA, Y Tabach, G Lourenço, and G Ruvkun. 2014. Identification of genes in toxicity pathways of trinucleotide repeat RNA in C. elegans toxicity. Nature Structural and Molecular Biology, 2014 Aug;21(8):712-20.
Liu, Y, PC Breen and G Ruvkun. 2014. Caenorhabditis elegans pathways that surveil and defend mitochondria. Nature. 2014 Apr 17;508(7496):406-10.
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