Why is it, that despite the thousands of genomes that have been sequenced, we cannot account for the heritability of most common traits and disease? Is it because many genes are involved? (Probably) or could there also be rules and genetic mechanisms that are still left to be discovered? (A much more intriguing possibility!)
It is currently unknown whether, how, and to what extent, heritable epigenetic information, and particularly heritable information that is carried by small RNAs, affects the inheritance of complex traits. We investigate mechanisms that enable epigenetic inheritance and soma-to-germline transmission of information.
Heritable information presents a unique opportunity for studying memory since it resides in specific cells (sperm or oocytes), and is amenable for biochemical characterization (e.g. sequencing). For example, we showed that memory of the parents’ dietary state can be recovered by sequencing starvation-responsive small RNAs that transmit to the children (and grand grandchildren), and regulate their gene expression. In addition, we discovered that inheritance of small RNAs obeys a set of rules, which are different but analogous to the rules that govern inheritance of DNA (Mendelian inheritance).
We focus our studies mostly, but not exclusively, on C.elegans nematodes, wonderful creatures that we find irresistible. C.elegans has a super-short generation time of just 3 days, and its nervous system is composed of just 302 neurons (and the entire “connectome” is mapped). These properties, combined with awesome genetic tools and unparalleled ease of cultivation, make the worm the ideal model organism for studying memory, and in particular heritable memory. Nevertheless, we are aware that other organisms have feelings too, and therefore try to make our studies as relevant as possible, so no one is offended.
"Can't start a fire without a spark"
"Can't start a fire without a spark"
Non-Mendelian genetics & Transgenerational epigenetic inheritance
Revolutionary discoveries in molecular biology, published in recent years, are making the once heretic idea of inheritance of acquired traits relevant again. Parental experiences, at least in worms, can affect the progeny’s physiology, sometimes permanently, or at least for multiple generations. In C.elegans, the mechanisms are being revealed, and the rate of progress is truly exciting. We are interested in inheritance of small RNAs, molecules that are actively shuttled between different tissues, and from the soma to the germline. We discovered that small RNAs are transcribed in response to different environmental stresses (Cell 2011, Cell 2014). We showed for the first time that heritable small RNAs are not diluted, since RNA-dependent RNA polymerases amplify the response in the progeny, in every generation (Cell 2011). Moreover, we recently discovered that a systemic feed back mechanism determines whether to “memorize the epigenetic response” (continue and transmit the ancestral information to additional generations), or whether to terminate the response, “forget” the memory, and rely once again on the hardwired genetic program (Cell 2016, Current biology 2017).
We were the first to show (Genes & Development, 2009) that functional small RNAs can move between interacting human cells (through the immunological synapse). We are motivated to discover whether the principles that govern epigenetic inheritance in C.elegans hold true also to mammals.
Molecular mechanisms for encoding of memory
We are interested in how information is represented in the nervous system, and how “the code” is implemented to produce behavior. In the broadest sense of the word, memory is what enables altering of future responses based on history. Many types of molecular mechanisms can retain memories in biological systems, for example, metabolic differences, epigenetic factors, stable bioelectrical circuit modes, or neuronal-circuits. We are studying how C.elegans, Planaria, and songbirds encode different types of memories. We are collaborating with computational neuroscientists, economists and linguists, trying to bridge the gaps between the type of neuroscience that is typically conducted by cognitive scientists, and the type of neuroscience that is typically studied by molecular biologists and geneticists. Specifically in C.elegans, since neuronal connectivity is largely hardwired and innate, it is very tempting to speculate that learning and memory are achieved by epigenetic mechanisms (or in the broad sense, mechanisms of gene regulation).
Evolution depends on variability and selection (and drift) . According to the classic interpretation of the “Modern synthesis” between Mendel, Darwin and the principles of population genetics, the environment enforces selection, but doesn’t affect variability. However, numerous epigenetic mechanisms that enable the environment to affect heritable variations are now known. We are studying whether and how epigenetic information can establish transient and stable variations, and as a consequence alter the rates of evolutionary processes. Moreover, since epigenetic effects can in theory allow adaptive changes in progeny, in response to parental reactions to environmental challenges, epigenetic inheritance has the potential ability to direct evolution’s path. To study these questions we are performing lab evolution experiments in a number of different model organisms, and record evolutionary processes as they take place.
We try very hard to let our curiosity guide us, and when the muse calls, we don’t get in its way. Because of that, we find ourselves studying many diverge subjects, including the mechanisms that allow toxoplasma parasites to control its host, translational read through, Pol III regulatory mechanisms, Ancient DNA, Fertility, Helmet formation in Daphnia, genome rearrangement in ciliates, polyploidy, development of new optogeneic tools,machine learning algorithms for automated phenotyping and decision making.
Lev I, Toker IA, Mor Y, Nitzan A, Weintraub G, Bhonkar O, Ben Shushan I, Seroussi U, Claycomb JM, Gingold H, Zaidel-Bar R, Rechavi O. Germ Granules Functions are Memorized by Transgenerationally Inherited Small RNAs. pre-print: bioRxiv.
Hakimi A#, Mor Y#, Toker IA, Levine A, Markovitz Y, Rechavi O. (2017) WorMachine: Machine Learning-Based Phenotypic Analysis Tool for Worms. BMC Biology.
Rechavi O. Lev I. (2017) Principles of Transgenerational Small RNA Inheritance in C. elegans. Current Biology.
* Corresponding author
*Houri-Ze'evi L, Korem Y, Sheftel H, Faigenbloom L, Toker IA, Dagan Y, Awad L, Degani L, Alon U, Rechavi O. (2016). A Tunable Mechanism Determines the Duration of the Transgenerational Small RNA Inheritance in C. elegans. Cell.
Rechavi, O., Kalman, M., Fang, Y., Vernitsky, H., Jacob-Hirsch, J., Foster, L. J., Kloog, Y., and Goldstein, I. (2010). Trans-SILAC: sorting out the non-cell-autonomous proteome. Nature Methods. 7:923-927.
Rechavi, O., Erlich, Y., Amram, H., Flomenblit, L., Karginov, F. V., Goldstein, I, Hannon, G. J., and Kloog, Y. (2009). Cell contact-dependent acquisition of cellular and viral nonautonomously encoded small RNAs. Genes & Development. 23:1971-1979.
A three-step MATLAB-based image analysis software developed in the Rechavi Lab that allows automated identification of C. elegans worms, extraction of morphological features, and quantification of fluorescent signals.