It’s been a big two weeks in the field of multigenerational effects in C. elegans with four different papers published or up on bioRxiv in a two-week window! Still reading all the new stuff, but why not shoot some initial thoughts into the void. That’s what Twitter is for, right?

Preface, this is obviously very early days in this field but whenever new papers in the field emerge (and especially 4!) my favourite thing to do is to try and place them within the broader field to look for common themes and mechanisms.

First up, Background! – Most observations of multigenerational effects in C. elegans, but not all, have “sprouted” from or been influenced by the small RNA inheritance field that dates back to the original Fire and Mello RNAi paper now published 22 years ago! #celegans #Ifeelold

To date all small RNA inheritance in C. elegans breaks into two categories (1) intergenerational effects on gene silencing in the soma that are controlled by NRDE-3 and (2) transgenerational silencing that is specific to germ cell gene expression only and is controlled by HRDE-1

The mechanisms regulating these effects are now relatively well-established, and given that three of the four new papers link multigenerational responses to the environment to small RNAs it’s probably fair to compare these new findings to this field. #smallRNAs

So, Theme thoughts!- My first thought having read these 4 new papers is that just like RNAi inheritance, the field of multigenerational responses to the environment is likely to also break into separate intergenerational and transgenerational fields, if it hasn’t already

Why do I think this? For starters, all intergenerational effects in C. elegans (2 or fewer gens) have either not been linked to small RNAs (so far) including the recent paper by @MfPez, @FranceMirko, @BenLehner or my own work or are NRDE-3 dependent like the new paper by @zaslab

By contrast, all the new transgenerational phenotypes like those reported by @LeahHouri @OdedRechavi and @rebeccasMoore1 @ctMurphy1 appear to be regulated by HRDE-1. Just like what we know about dsRNA inheritance from the Kennedy/Miska/Mello labs and others.

This leads to a cool new potential “rule” (?) (In the theme of the new @OdedRechavi paper). – Intergenerational responses in C. elegans might not be mediated by small RNAs, but transgen ones (so far) are, and should (?) function like what we know about HRDE-1 based inheritance

However, this also raises many interesting questions for this new field. For example, How does HRDE-1 mediate transgenerational effects if the small RNAs HRDE-1 binds never leave the germline? Presumably there is some signal/hormone coming from germ cells? What could it be?

Second question - If there is a signal coming out from the germline and it is NOT small RNA (or RNA at all), then what provides the specificity of the response?

Third question – Why do animals so strongly separate intergenerational responses from transgenerational responses? This includes apparently evolving separate mechanisms for these two processes? Maybe no answers yet, but I suspect this will be the future of the field.

Fun fact of history, when I was in the Kennedy Lab working on dsRNA inheritance, I remember making the discovery that NRDE-3 mediated inheritance only lasted on generation, but some other NRDE-1/2 mediated mechanism controlled transgen silencing

At the time, I got chose to focus on NRDE-3 mediated inheritance because it inherited gene silencing of somatically expressed genes which I suspected were more likely to be involved in environmental response. These new papers suggest that hypothesis is not true! Science!

I have MANY more thoughts on this third question but am saving them for about two months from now when (hopefully) I will add yet another paper to this field (on bioRxiv) looking at the evolution of these responses across different species to try and answer this (stay tuned!)

I will also likely continue to speculate on all these new findings as they take twitter by storm (and I think more), maybe I’ll post them here, maybe I’ll make a new thread, either way it’s extremely fun to be part of a field as it emerges. Chime in if you have thoughts!