RESEARCH HIGHLIGHTSNON-CODING RNASPIWI’s new assistantan integralrole forGTSF1 in thePiwi–piRNA
pathway

PIWI-interacting RNA (piRNA)-mediatedsilencing of transposable elements isone of many mechanisms used by animalcells to safeguard genomic integrity, astransposons can disrupt genes and alter
the genome. Recent work identifies
a protein — originally called Asterix
and referred to as gametocyte-specificfactor 1 (GTSF1) in two subsequentstudies — that is a key cofactor ofpiRNA-mediated transcriptionalsilencing in Drosophila melanogaster.
piRNAs are non-coding RNAs thatassociate with PIWI proteins, of which
there are three in D. melano­gaster:
the cytoplasmic Aubergine andArgonaute 3, and the nuclear Piwi.
Piwi interacts with piRNAs in thecytoplasm, forming a complex that is

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imported into the nucleus to mediatetranscriptional silencing of transposons
that are complementary to the piRNAs.
However, the underlying mechanism
and the precise composition of thenuclear silencing complex are notfully understood.
Previous work had shown that GTSF1
is required for transposon silencing
in mouse testes. Muerdter et al.,Ohtani et al. and Dönertas et al. knocked
down the homologue of GTSF1 inD. melanogaster and found that thisblocked silencing of piRNA-targeted
transposons. Interestingly, the phenotypeof D. melanogaster lacking GTSF1 wascomparable to those of Piwi–piRNA
pathway mutants. These findings
suggest a key role for GTSF1 intransposon silencing as part of thePiwi–piRNA pathway.
The groups sought to identify which
step of the piRNA pathway GTSF1 isinvolved in. They found that loss ofGTSF1 did not affect piRNA levels or
Piwi–piRNA localization, indicating that
it is not involved in piRNA biogenesis or
nuclear import of the complex. Instead,
GTSF1 interacts with Piwi in vitro, andthe two proteins colocalize in the nucleiof D. melanogaster ovarian cells in vivo.
Thus, GTSF1 might act as a cofactor
in the silencing process. Notably,
Dönertas et al. found that GTSF1 does
not interact with Piwi through its CHHC
zinc-finger motifs (which Ohtani et al.
show are required for its activity) butthrough its carboxyl terminus.

NATURE REVIEWS | MOLECULAR CELL BIOLOGY

Piwi mutants show a significant
increase in RNA polymerase II occupancy(a sign of active transcription) anddecreased levels of the repressive
mark trimethylated histone 3 at Lys 9(H3K9me3) at transposons. Importantly,
Ohtani et al. and Dönertas et al.
observed that knockdown of GTSF1
increased RNA polymerase II occupancy.
Moreover, all three groups observed
decreased enrichment of H3K9me3
at Piwi-repressed transposons, which,
together with the increased RNA
polymerase II occupancy, is similar towhat has been observed in Piwi mutants.
These studies reveal an integral rolefor GTSF1 in the Piwi–piRNA pathway,
acting during transcriptional silencing oftransposons. Further work is now needed
to determine the exact role of GTSF1 inthe silencing complex.
Rachel DavidORIGINAL RESEARCH PAPERS Muerdter, F. et al.
A genome-wide RNAi screen draws a genetic
framework for transposon control and primarypiRNA biogenesis in Drosophila. Mol. Cell 50,
736–748 (2013) | Ohtani, H. et al. DmGTSF1 isnecessary for Piwi–piRISC-mediatedtranscriptional transposon silencing in theDrosophila ovary. Genes Dev. 27, 1656–1661(2013) | Dönertas, D., Sienski, G. & Brennecke J.
Drosophila Gtsf1 is an essential component of thePiwi-mediated transcriptional silencing complex.
Genes Dev. 27, 1693–1705 (2013)
FURTHER READING Czech, B. et al. A
transcriptome-wide RNAi screen in the Drosophila
ovary reveals factors of the germline piRNA
pathway. Mol. Cell 50, 749–761 (2013) | Siomi, M. C.
et al. PIWI-interacting small RNAs: the vanguard ofgenome defence. Nature Rev. Mol. Cell Biol. 12,246–258 (2011)

VOLUME 14 | SEPTEMBER 2013
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