While some studies may appear as drops in the scientific ocean, a drop-dead gorgeous paper on epigenetic inheritance recently made us all drop our guard! Although studies have established transgenerational epigenetic inheritance (TEI) across several generations in the nematode worm Caenorhabditis elegans and the critical role of non-coding RNAs, we have yet to unravel the exact mechanisms behind RNA-mediated TEI. Towards this goal, researchers from the lab of Scott Kennedy (Harvard Medical School, Boston, MA, USA) recently dropped everything to take on this task.
Fascinatingly, the talented team demonstrates that the precise formation of intracellular liquid droplets in space and time helps to control RNA-directed TEI!
Here’s all the information on this elegant new C. elegans study:
- Initial screens to identify factors required for RNA inheritance identified the C. elegans ZNFX-1 homolog (RNA helicase) and WAGO-4 (Argonaute factor) as essential pieces of the puzzle
- ZNFX-1 and WAGO-4 localize to germ granules (P granules) in early germline blastomeres
- Loss of ZNFX-1 or WAGO-4 causes progeny to lose the ability to inherit RNA-mediated silencing
- Further analysis suggests that WAGO-4 aids the RNAi-directed interaction of ZNFX-1 with mRNAs undergoing heritable silencing
- However, while ZNFX-1 and WAGO-4 localize to P granules in early germline blastomeres, ZNFX-1 and WAGO-4 separate from P granules to form a distinct liquid droplet, which the authors termed the “Z granule”, to coincide with germline transcription
- Separation might be triggered when newly synthesized mRNAs pass through P granules and interact with RNA-binding proteins to alter local protein concentrations
- The Z granule may concentrate/segregate silencing factors into the germline to promote RNA-based TEI
- After further development, Z granules assemble into an ordered tri-droplet grouping with two similar liquid droplet foci (P granules and Mutatorfoci) to form “PZM granules” In adult germ cells
- Z granules may act as a “bridge” between P granules and Mutator foci in adult germ cells
- Data suggests that RNA-directed TEI requires correct PZM assembly, both in space and time
The group now hopes to understand how the PZM assembles correctly, how the PZM contributes to RNA-based TEI, if further distinct droplets may be involved, and if other cells use a similar space and time separation system to control gene regulatory or biochemical pathways.
Senior author Scott Kennedy concludes, “It’s exciting to see three liquid droplets take shape within a fourth liquid, forming ordered configurations and not mixing with one another—that’s pretty wild for a number of reasons. This could be a system by which you order it, so A happens before B happens before C”.
For more on how these little drops of liquid could be critical determinants of RNA-mediated TEI, see Nature, May 2018.