While a “bird’s-eye view” of a topic can often provide colossal insight, the opposite perspective can sometimes be just as useful! Recently, two fascinating studies of transgenerational epigenetic inheritance have taken a “worm’s-eye view” of this research area to deepen our understanding of this complex mechanism in the model nematode worm C. elegans.
C. elegans employ small RNAs that mediate RNA interference (RNAi) for the heritable regulation of gene expression, and new research now describes the rules governing transgenerational epigenetic inheritance and demonstrates how this mechanism mediates pathogen avoidance and the inheritance of this behavior.
Laying Down the Laws that Control Variability in Transgenerational Epigenetic Inheritance
While one C. elegans may look just like another to the naked eye, individuals exhibit their own “personality.” Worm one may be a huge Dune fan, but worm two could prefer Ursula K. Le Guin over Frank Herbert. Additional differences include developmental timing, behavior, lifespan, and the epigenetically inherited regulation of gene expression; however, we lack an understanding of why. For example, some progeny maintain the long-term epigenetic gene silencing inherited from their mothers, while others lose gene silencing effects more quickly.
Now, well-read researchers led by Leah Houri-Ze’evi and Oded Rechavi (Tel Aviv University, Israel) lay down the law and describe the basic rules that control how differences in transgenerational epigenetic inheritance arise in similar C. elegans individuals. Excitingly, the authors also demonstrate how understanding these laws helps to predict the response of progeny to a stressor, which impacts small RNA inheritance dynamics, given knowledge regarding their mother’s “inheritance state.”
So, let’s read on and hear all the details from Houri-Ze’evi and colleagues!
- Analysis of fluorescent transgene-silencing induced by double-stranded RNA in 20,000 engineered C. elegans individuals and their progeny permitted the derivation of three basic “laws” regarding transgenerational epigenetic inheritance
- First law: While inherited gene silencing effects dissipate, progeny from the same mother display the same degree of silencing
- Second law: Progeny from different mothers display differing randomly assumed gene-silencing behavior, which correlates with the mother’s inheritance state
- Third law: Those worm lineages displaying longer ongoing inherited epigenetic gene silencing are more likely to pass gene silencing behavior to their progeny
- Gene and small RNA expression profiles in individual worms with differing inherited gene-silencing behaviors highlights a role for the heat shock factor 1 (HSF-1) transcription factor in determining the mother’s inheritance state
- Interestingly, mathematical modeling of transgenerational epigenetic inheritance that incorporates the three laws and the mother’s inheritance state allows the prediction of how progeny respond to external stress-inducing stimuli
Overall, the founding of fundamental laws and the resultant predictive model provides colossal insight into transgenerational epigenetic inheritance, taking us one massive step towards a fuller understanding of this fascinating small RNA-mediated process.
Study leader Oded Rechavi concludes, “The worms changed the rules by showing us that inheritance outside the genetic sequence does exist, via small RNA molecules, enabling parents to prepare their offspring for the difficulties they have encountered in their lifetime. From one study to the next we shed light on the molecular mechanisms and mysterious dynamics of epigenetic inheritance, with the present study providing laws and introducing some ‘order into the chaos.”
Bacterial Small RNA Helps Mom to Tell the Kids What’s Off the Menu!
While C. elegans love nothing more than to worm around and scoff down Pseudomonas bacteria, they fall ill and quickly learn to avoid devouring the unpalatable pathogenic strains present in their environment. Interestingly, any C. elegans “mom” unlucky enough to eat a delectable but dangerous microorganismal snack can also let their “kids” know what is strictly off the menu; however, the mechanism involved has remained somewhat of a mystery.
Now, a scientifically ravenous group of researchers led by Coleen T. Murphy (Princeton University, New Jersey, USA) has established that a small RNA (P11) derived from a pathogenic Pseudomonas straininduces pathogen avoidance behavior in C. elegans and the transgenerational propagation of this behavior down the generations.
So, what did Kaletsky and colleagues discover about mechanisms behind the learned eating habits of C. elegans?
- Small RNA, but not DNA or larger RNA species, from a pathogenic Pseudomonas strain induces pathogen avoidance behavior in C. elegans through a mechanism independent of viral or microRNA pathways
- The ingestion of a pathogenic Pseudomonas strain leads to the uptake of P11 in the C. elegans intestine
- This stage requires the double-stranded RNA transporter SID-2 and the double-stranded RNA endoribonuclease DCR1, respectively, which are components of the RNAi system
- Importantly, P11 then passes through a germline stage involving PIWI-interacting RNA pathway processing and P granule function before communication with the ASI sensory neuron of C. elegans
- In this neuron, P11 downregulates maco-1 gene expression (which functions in chemotaxis, thermotaxis, oxygen sensing, and neuronal excitability) to upregulate the expression of the TGF-β ligand daf-7 to induce maternal avoidance behavior
- However, the prior passage of P11 through the germline also induces the inheritance of pathogen avoidance behavior to progeny
Overall, the author’s mouthwatering model states that P11 acts on the ASI neuron of the C. elegans “mom” to alert of the ingested pathogen; however, the journey through the germline allows this information to be passed down the generations to let the kids know what seemingly appetizing bacteria may make their stomachs turn!
Lead author Coleen Murphy summarizes, “Instead of a signal from the metabolites that the bacteria produce, as we had originally expected, we found that the worms ‘read’ the small RNAs that bacteria make, particularly small RNAs that correlate with the pathogenic state of the bacteria. The P11 small RNA itself doesn’t even make the worms sick – just detecting the presence of P11 is enough to make the worms avoid the bacteria, and to pass it on to four generations of progeny.”
A Worm’s-eye View of Transgenerational Epigenetic Inheritance
They say that the early bird catches the worm, but any interested avian species will have to pull an all-nighter to keep up with the teams behind these awe-inspiring C. elegans-based studies on transgenerational epigenetic inheritance. Looking forward, research aims in this area include the exploration of transgenerational epigenetic inheritance in other organisms and the further exploration of how small RNAs can lead to adaptive transgenerational changes in behaviors.