ReseaRch highlights

Nature Reviews Molecular Cell Biology | aop, published online 10 march 2010; doi:10.1038/nrm2872
small RNas

Chicken or egg?
RNA interference (RNAi) pathways mediate gene present in Dcr1- and Rdp1-depleted cells.
silencing by promoting translational inhibition or High-throughput sequencing experiments showed
RNA degradation, and also act at the DNA level that many of these small RNAs derive from dg and
by repressing transposon activity and promoting dh repeats, thus showing that heterochromatin,
the assembly of heterochromatin. Interestingly, Dcr1 and Rdp1 are not required for the initial
however, the biogenesis of small interfering RNAs accumulation of small RNAs — which have been
(siRNAs), which direct heterochromatin formation, termed priRNAs — at these repeat target sites.
is itself dependent on factors associated with Heterochromatin mutants with functional
heterochromatin. So which came first? Now, in Dcr1 and Rdp1 accumulated high levels of dg
Cell, Halic and Moazed show that a distinct class repeat siRNAs. This amplification requires the
of small RNAs, called primal small RNAs (priRNAs), RNA cleavage activity of Ago1, suggesting that
initiates the amplification of siRNAs in the an Ago-dependent pathway leads to siRNA
absence of heterochromatin, which in turn amplification without the requirement of
induce heterochromatin formation. pre-existing heterochromatin, and that priRNAs
The authors used Schizosaccharomyces might function as the initial trigger for siRNA
pombe as a model for investigating RNAi and amplification.
heterochromatin interactions at pericentromeric The authors also found that Ago1 promotes
regions, which contain dg and dh repeat elements. low levels of H3K9 methylation at centromeric
The RNAi machinery core components are DNA in the absence of siRNA amplification.
Argonaute 1 (Ago1), RNA-dependent RNA This function is dependent on the ability of
polymerase 1 (Rdp1) and Dicer 1 (Dcr1). Dcr1 Ago1 to bind priRNAs, thus suggesting that
processes double-stranded RNA (dsRNA) priRNAs also trigger heterochromatin assembly.
into siRNAs, which are loaded onto The fact that priRNAs are enriched in the
Ago1 and guide the RNA-induced 3′ ends of annotated transcripts and
transcriptional silencing (RITS) depend on a partially functional exosome
complex to target sequences suggested that priRNAs might result
through the interaction of from RNA processing events
siRNAs in Ago1 with associated with transcription
nascent RNAs. The RITS termination and that they are
complex associates degradation products of
with chromatin by single-stranded transcripts that
binding histone H3 bind Ago1.
Lys9 (H3K9)-methylated This study defines a new
nucleosomes and class of Dicer-independent
recruits the H3K9 small RNAs that function in
methyltransferase Clr4 an Ago-dependent manner to
and the heterochromatin trigger siRNA amplification and
protein 1 homologue Swi6. heterochromatin formation. The authors
The silencing signal is argue that priRNAs might associate
amplified by the action of randomly with Ago1 and function as a
Rdp1 on heterochromatin-bound surveillance mechanism for abundant
transcripts and the processing transcripts. However, the detailed
of the resulting dsRNA mechanisms of priRNA
into siRNAs. biogenesis and whether this
Halic and Moazed process is regulated
found that in remain to be determined.
Clr4-deficient mutant Kim Baumann
strains that lack
ORIGINal REsEaRCH PaPER
heterochromatin, Halic, M. & Moazed, D. Dicer-
siRNA levels were independent primal RNAs trigger
strongly reduced, but RNAi and heterochromatin
formation. Cell 140, 504–516 (2010)
Ago1 was nevertheless fuRtHER REadING Hutvagner, G. &
able to bind small RNAs. Simard, M. J. Argonaute proteins: key
players in RNA silencing. Nature Rev. Mol. Cell
Likewise, low levels of
Biol. 9, 22–32 (2008)
Ago1-bound small RNAs were

nature reviews | MoleCular Cell Biology volume 11 | april 2010

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