12.2019 | THE SCIENTIST 39© PEG GERRITY
gene regulation is important in immune
responses to many types of infection,
and it helps cells when mitochondria
get stressed by regulating mRNAs that
encode key mitochondrial proteins.^13
The story that has emerged is that
paraspeckles act as buffers when cells
are stressed, helping them maintain
homeostasis and avoid apoptosis. This
function is likely useful for long-lived
cells such as neurons, but also may play
a role in some types of tumor forma-
tion. The role of paraspeckles in cancer
is still an active area of study, however,
and thus far there are conflicting data
in different cancer types. While one big
study found that paraspeckles may be
oncogenic,^14 another paper found that
the structures can actually suppress can-
cer.^15 Nevertheless, it appears that para-
speckles can be both good and bad when
it comes to disease.Getting in phase with disorder
Even with all the excitement about
the NEAT1 RNA, I never lost focus on
the paraspeckle proteins that are also
needed for these little structures to
form. In 2012, Hirose and colleagues
published a landmark paper expand-
ing the paraspeckle proteome from the
three I originally found up to a total of
40 different protein types.^16
My postdoc Sven Hennig and I
teamed up with Hirose to interrogate
the interactions among these mol-
ecules and found that some parts of
the proteins with no predicted struc-
ture, called low complexity domains,
were very important. In collaboration
with Charlie Bond, also at the Univer-
sity of Western Australia, we showed
that the low complexity domains of the
paraspeckle proteins formed hydrogels,
jelly-like globs that are neither liquid
nor solid, implicating these proteins in
the phenomenon of liquid-liquid phase
separation (LLPS).^17 LLPS is a hot new
area in cell biology, and it may eventu-
ally explain how cellular structures and
macromolecular complexes form with-
out membranes to compartmentalize
the cytoplasm and nucleus.In the case of paraspeckles, after bind-
ing to NEAT1, proteins self-associate
and recruit other paraspeckle proteins
that glue RNA-protein particles into a
mature paraspeckle.^18 While the mate-
rial properties of paraspeckles are still
being worked out, I anticipate that our
wealth of knowledge about their com-
position and organization will make
them highly attractive as a model mem-
braneless organelle to help scientists
gain new ground in continuing research
on phase separation.
My hope for paraspeckle biology is
that we will one day have a complete
molecular model of a paraspeckle, down
to the atomic level, with a full suite of
molecular tools to break it down and
build it up. With a better understand-
ing of why cells make paraspeckles, espe-
cially when stressed, we could in theory
use these tools therapeutically to modu-
late the structures in different diseases.
Although we have learned a lot since
the discovery of paraspeckles nearly two
decades ago due to the hard work and
creativity of the members of my and
other research groups, there is undoubt-
edly much more to understand. I look for-
ward to being part of that adventure. gArcha Fox is an associate professor and
Australian Research Council Future
Fellow at the University of Western Aus-
tralia and an affiliate with the Harry
Perkins Institute of Medical Research.References- A.H. Fox et al., “Paraspeckles: A novel nuclear
domain,” Curr Biol, 12:13–25, 2002. - A.H. Fox et al., “P54nrb forms a heterodimer
with PSP1 that localizes to paraspeckles in
an RNA-dependent manner,” Mol Biol Cell,
16:5304–15, 2005. - K .V. Prasanth et al., “Regulating gene
expression through RNA nuclear retention,”
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for a nuclear noncoding RNA: NEAT1 RNA
is essential for the structure of paraspeckles,”
Mol Cell, 33:717–26, 2009. - H. Sunwoo et al., “MEN epsilon/beta nuclear-
retained non-coding RNAs are up-regulated
upon muscle differentiation and are essential
components of paraspeckles,” Genome Res,
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lincRNA essential for transformation
suppression,” Genes Dev, 31:1095–108, 2017. - T. Naganuma et al., “Alternative 3’-end
processing of long noncoding RNA initiates
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