Oded Rechavi
Krill Prize 2015
Tel Aviv University
Oded Rechavi
Research Topic:
Epigenetic inheritance and its effect on the process of evolution
We use the relative simplicity and genetic tractability of different model organisms, mostly the nematode C.elegans, to discover novel biological principles by which RNA affects formation and inheritance of complex traits, and to study memory encoding in the nervous system. In general, the human genome project has failed so far to revolutionize diagnosis (Danchin et al. 2011). While linking rare Mendelian traits to specific sequence variations has been accelerated, the genetic basis of many common diseases is not understood despite the undertaking of many genome wide association studies. It appears that our current genetic models fall short of faithfully explaining the inheritance of most complex traits. The inheritance of acquired characteristics is a topic of long-standing interest and controversy. While some of the classic Lamarckian ideas have been dismissed (Weismann 1889), more recent studies suggest that certain traits acquired by an animal during its lifetime may be transmitted to next generations. Using a viral infection model I discovered in my post doc that C.elegans inherit acquired antiviral resistance (in a “Lamarckian” fashion) and also deciphered the molecular mechanisms that underlie this inheritance (Rechavi al, Cell 2011). Such unusual genetics occurs through transgenerational transmission of small RNAs, which mediate RNA interference (RNAi). My study showed that antiviral RNAs (viRNAs), which protect the worm from viral propagation, can be transmitted from the soma to the germline and pass down to many ensuing generations in a non- Mendelian manner, in the absence of their DNA template, and thus protect (“vaccinate”) RNAi-deficient progeny from viral propagation. Most genes are regulated by different endogenous regulatory small RNA species (Salmena et al.
2011), and therefore small RNA inheritance might affect the inheritance of many traits. Indeed, in my new lab in Tel Aviv we recently found that starvation-induced developmental arrest produces a transgenerational signal in the form of small RNAs, which prolongs for multiple generations, regulates nutrition-related genes, and as a result extends the progeny’s lifespan (Cell, 2014). We discovered that the RNA binding protein RDE-4 is required for the production of the implicated small RNAs in the starved eneration and that the argonaute protein HRDE-1 (heritable RNAi deficient) is required for inheritance of these small RNAs. In the past we identified RRF-1 as the RNA dependent RNA polymerase that amplifies heritable small RNAs in every inheriting generation to prevent dilution of the heritable small RNA response. We are currently characterizing additional components in the RNA inheritance machinery (papers in preparation), define additional environmental conditions that produce heritable effects (several papers in preparation), and also extend our findings to additional organisms (protists, daphnia and others). In addition, we are preforming lab evolution experiments in a number of species to catch “in the act” the long-term effects of heritable RNAi. Also, we define the genetic boundaries between interacting organisms, or the conditions that allow breaching of such barriers. For example, we recently found that piRNAs, unlike other genes, cannot be cloned in E.coli, an organism on which C.elegans worms feeds in the lab, which is capable of transmitting small RNAs to C.elegans (Frontiers in genetics, 2014). We examine the intriguing possibility that worms and bacteria naturally exchange small RNAs between them both as a defense mechanism, and as a form of interspecies communication. The worm’s immune system is coordinated by its nervous system (Kao et al, 2008), therefore, we examine whether systemic spreading of small RNAs is involved in such coordination, and if so, whether such regulation transmits transgenerationally. To
study these complex phenomena, we developed novel methods for single-cell transcriptome profiling, and functional assays for dissecting neuronal circuits. We previously showed that small RNAs (Rechavi et al, 2009 Genes & Development) and
other macromolecules (Rechavi et al, 2010 Nature Methods) are exchanged between human immune cells when immunological synapses are transiently formed. Therefore, transgenerational inheritance of acquired traits may be widely conserved
