Thread by @OdedRechavi

💥🎉 FINALLY! Our paper is out! 💥🎉 @CellCellPress We discovered that the nervous system of C.elegans transmits information via small RNAs across multiple generations to control the behavior of the progeny. A thread 👇👇(1/17) #molecularmemories
cell.com/cell/fulltext/…

First, I’d like to congratulate @rlipo2 & @Toker_IA the amazing PhD students that led the work. This was an multi-person extreme effort, many years of very hard work. This beautiful illustration was drawn by Beata Edyta Mierzwa @beatascienceart (2/17) 👇

Many have speculated, ever since antiquity, that brain activity could
somehow generate heritable changes that would impact the fate of the next
generations. But transgenerational epigenetic inheritance is still extremely controversial, especially in mammals. (3/17)👇

The reason it’s controversial is that there’s no good mechanism that can explain it. It was hypothesized a long time ago (19th century) that the germline is isolated from the soma, and that somatic responses (including neuronal responses) cannot become heritable. (4/17)👇

In C.elegans nematodes, however, the “Weismann Barrier” is breached & transgenerational inheritance does happen. Aside from DNA the worms inherit small RNAs (!!) We learned a lot about the mechanisms over the years, see this review:
ncbi.nlm.nih.gov/pubmed/28743023 (5/17)👇

While we knew exogenous *artificial* small RNAs can move between cells and across generations, it wasn’t known whether somatic endogenous (natural) small RNAs can affect the next generations. Specifically, it wasn’t known if neurons can affect the progeny via small RNAs (6/17)👇

To test if neuronal small RNAs can affect the progeny, we generated worms that synthesize RDE-4-dependent small RNAs only in neurons, and sequenced small RNAs from isolated neurons (for the first time) and from gonads (the target tissue containing inherited information) (7/17)👇

Then we isolated rde-4 mutant progeny that derive from ancestors that had rde-4 expressed only in neurons, and tested whether RDE-4-dependent small RNAs got inherited (8/17)👇

We found that expressing RDE-4 in the nervous system of the parents leads to the generation of small RNAs inherited in the germline across multiple generations. Further, these germline small RNAs regulate their target genes transgenerationally via the argonaute HRDE-1. (9/17)👇

We examined whether the heritable small RNAs regulate their targets using mRNA sequencing and also single-molecule FISH. But before I get to the specific genes (wait patiently), you are probably asking yourself: “What’s the physiological relevance??” (10/17)👇

We discovered that rde-4 mutants are bad at finding food in high temperatures. By recording the mutants’ neuronal activity, we found that they can smell OK, but something downstream doesn’t work well. If you restore RDE-4 to neurons, they are fine. (11/17)👇

MORE interestingly, if rde-4 great-grandchildren are derived from heterozygous great-grandparents that expressed rde-4 only in neurons, their chemotaxis behavior is much improved. The ancestors’ neurons control the behavior of the great-grandchildren (12/17)👇

Does this mean that the heritable small RNAs move from the germline back to the neurons of the progeny? Not necessarily. We have evidence that regulation of germline genes in the progeny controls behavior transgenerationally (13/17)👇

We find that the germline-specific argonaute HRDE-1 is required for the heritable control over behavior and that transgenerationally regulated genes express in the germline. How can you affect behavior by regulating the germline? Think of castrated dogs. (14/17)👇

Importantly, we zoomed in on the transgenerationally regulated genes and identified saeg-2 as required for the heritable control over behavior. When we CRISPR saeg-2 out we correct the behavior of the mutant. (15/17)👇

Here’s a summary model, illustrated by Dror Cohen (16/17)👇

There’s much more so go read the paper!
cell.com/cell/fulltext/…
I’ll add also that in the same issue @cell there’s a fascinating paper from @ctmurphy1 on transgenerational learned pathogenic avoidance (different story, but conceptually related) (17/17)
cell.com/cell/fulltext/…

Here’s another version (better resolution also) of the beautiful artwork done by @beatascienceart

https://twitter.com/beatascienceart/status/1136657471949328384?s=21