The amazing travels of small RNAs

Date:
July 28, 2020
Source:
ETH Zurich
Summary:
Biologists have known for some time that RNA interference can
silence genes in far-off cells. They suspected that a messenger
substance 'transmits' RNA interference. Now, researchers have
definitively shown that these messengers in plants are short
double-stranded RNA fragments.



FULL STORY ==========================================================================
In most organisms, small bits of RNA play a key role in gene regulation
by silencing gene expression. They do this by targeting and docking
onto complementary sequences of gene transcripts (also RNA molecules),
which stops the cell machinery from using them to make proteins. This
mechanism is called RNA interference (RNAi), and it is critically
important in biology.


========================================================================== Remarkably, the RNAi phenomenon is not necessarily confined to single
cells; it can also manifest in other tissues and organs far away from
the cell of origin.

Researchers have been able to observe it mostly in plants, but also in
"lower" animals such as the nematode worm C. elegans.

Proteins and DNA ruled out Still, one key question had so far gone
unanswered: which messenger substance traverses cells and tissues? "We
were able to rule out proteins 20 years ago, once it was discovered
that RNAi can travel in plants," says Olivier Voinnet, Professor of
RNA Biology at ETH Zurich. RNAi requires that the messenger docks to a complementary sequence of the gene transcript to be silenced. "Proteins
alone don't have this capability. DNA leaving the cell nucleus is also unlikely," Voinnet continues. "The most likely candidate has always been
an RNA molecule." What has been unclear until now is which precise type
and form of RNA -- long, short, single- or double-stranded, bound to
proteins or not.

Double-stranded fragments travel far and wide But now, the ETH researchers
are shedding light on this process in a new study.

They are the first to demonstrate unequivocally that these distant
messengers in plants are short double?stranded RNA molecules. These
consist of pairs (or double-strands) of just 21 to 24 nucleotides (the
building blocks of RNA) called small interfering RNAs, or siRNAs for
short. The team's paper was recently published in the journal Nature
Plants.



========================================================================== siRNAs usually emerge as large and complex populations from the genomes
of viruses that have infected a cell. But a cell's own genes can also
serve as blueprints for these molecules. As a result, cells can use RNAi
to silence not only invading viruses but also their own genes.

Because RNAi moves, plants have the amazing capacity to modulate gene expression at a distance. This might be particularly important for them
to constantly adapt their new growth, enabling what is called "phenotypic plasticity." To move or not to move In their new study, the researchers
ruled out the possibility that other types of nucleic acids or complexes composed of RNA and proteins move across plant cells. "We can definitively
show that double?stranded siRNAs are necessary and sufficient to induce
RNAi in distant cells and tissues of plants," Voinnet says.

Not only did the ETH researchers identify the elusive long-distance
messengers, they also show, in their study, how siRNAs move and carry
out their function.

They found that, as long as an siRNA molecule exists as a free
double-strand, it is mobile because it cannot bind to a matching RNA transcript. To bind, it first has to be "uploaded" to a specific Argonaute (AGO) effector protein. Only once bound to the correct AGO protein can
the siRNA silence the target transcript; the process eventually destroys
the fragment itself. The model plant used for the study has ten different
AGO proteins, several of which recognise matching siRNA fragments with
specific signatures; these signatures are not homogeneous among the large cohorts of mobile siRNAs produced from viruses or the plant's own genes.



==========================================================================
AGO proteins determine siRNA movement patterns Different AGO proteins
occur in distinct cells and tissues. The ETH researchers found that
as part of the uploading process, matching AGO proteins "consume" a
fraction of siRNAs in the cell of origin, but the non-loaded fraction
can exit the cell.

Depending on the presence or absence of certain AGO proteins within
the cells traversed by the mobile siRNAs, the molecules, again, will be consumed or not.

For example, if there are a plethora of AGO proteins on hand, they will
trap plenty of siRNAs with various signatures, essentially stopping
movement. If a cell contains hardly any AGO, on the other hand, then
most siRNAs will leave and travel greater distances. And finally, if
a cell contains large quantities of only one specific AGO, then only
those siRNAs with the matching signature will be consumed, while the
others will move. In other words, siRNAs are selectively filtered and
consumed as they make their way through the plant tissue.

Until now, the plant RNAi community had thought that RNAi moves along
linear gradients. However, this does not take into account that AGO
proteins selectively use up some siRNAs -- but not others -- as they
move. The new study points out that this consumption process is, in fact, anything but linear.

Countless movement patterns "The amount and diversity of AGO proteins
in traversed cells coupled to the siRNA-intrinsic signatures function
together as a kind of molecular sieve, the form of which may differ from
cell type to cell type along the siRNA path.

Depending on the spatial configuration of this sieve, a wide variety of
siRNA movement patterns can be produced," Voinnet explains. He adds: "Even
more interestingly, some AGOs can be induced by stress or developmental
signals such that the spatial shape of the sieve can change and evolve
at any given time." The countless movement patterns thus lend the mobile
RNAi system almost boundless flexibility and versatility in shaping gene expression across distances. Now that they have understood the process,
the team of researchers is trying to engineer artificial sieves in plants
as a way to control, with high precision, when and where specific siRNAs
can move, a method which could have applications in agriculture.


========================================================================== Story Source: Materials provided by ETH_Zurich. Original written by
Peter Ru"egg. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Emanuel A. Devers, Christopher A. Brosnan, Alexis Sarazin, Daniele
Albertini, Andrea C. Amsler, Florian Brioudes, Pauline
E. Jullien, Peiqi Lim, Gregory Schott, Olivier Voinnet. Movement
and differential consumption of short interfering RNA duplexes
underlie mobile RNA interference. Nature Plants, 2020; 6 (7):
789 DOI: 10.1038/s41477-020- 0687-2 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/07/200728113516.htm

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