12.2019 | THE SCIENTIST 35With a better
understanding of
why cells make
paraspeckles, we
could in theory
therapeutically
modulate the
structures.
same family as PSPC1—were also enriched
within paraspeckles.^2 While PSPC1 was an
unstudied protein at the time I named it,
scientists knew that NONO and SFPQ
played roles in gene regulation and RNA
processing. It soon became obvious that
RNA was a major component of para-
speckles, and various RNAs were inte-
gral to their formation. Treating cells with
RNases made PSPC1, NONO, and SFPQ
disappear from paraspeckles, showing it
was RNA holding the proteins there. The
picture emerged that paraspeckles were
conglomerations of protein and RNA that
were formed and maintained by what we
now know as phase separation dynamics,
a physical process that made them part of
a group of cellular structures known as
membraneless organelles. (See “Cellular
Droplets,” The Scientist, December 2018.)
I often saw paraspeckles in clusters on
one side of the nucleus, and I could also see
that only some of the HeLa cells’ micronu-
clei—small structures that carry fragments
of chromosomes—had paraspeckles. Some
nuclei must contain paraspeckle-forming
DNA, while others did not, Angus and I
thought; a particular part of the genome,
maybe even a specific gene, might be caus-
ing paraspeckles to form. But the identity
of that DNA was a mystery.
The period following my initial dis-
covery in the early 2000s was a lonely
time in paraspeckles research. Besides
our group, there was only one other lab
interested in paraspeckles—that of David
Spector at Cold Spring Harbor Labora-
tory. A few years after our initial para-
speckle publication, independent work
from his group found that NONO-bound
RNA was retained in the nucleus, unable
to enter the cytoplasm, where it could be
translated into a protein.^3 Then, in 2005,
I received an email from Gérard Pierron
at France’s National Center for Scientific
Research (CNRS) near Paris.
Pierron wondered if paraspeckles might
correspond to structures that his group had
first observed with electron microscopy in
the early 1990s. At the time, the researchers
called the structures inter-chromatin
granule associated zones. These were mor-
phologically distinct from the rest of the
nuclear material, or nucleoplasm, but did
not have a molecular marker to distinguish
them. I sent Pierron some antibody to
PSPC1, which he tested against HeLa cells
in his lab. Sure enough, he could see enrich-
ment in the zones identified by electron
microscopy, suggesting that these granules
were indeed paraspeckles.
So actually, the French group had been
the first to see and publish on what would
later become known as paraspeckles—
and suddenly I was not so alone.A NEAT link
In 2007, after I left Angus’s lab to start
my own group at the University of West-
ern Australia, I got another email about
my paraspeckle work. Jeanne Lawrence,
an epigenetics researcher based at the
University of Massachusetts Medical
School, requested some antibody to
PSPC1. I happily shared my reagents,
and then I did not think much more
about it, until a few months later when
Lawrence contacted me again to see if I
was interested in a collaboration.
Her group was working on a
lncRNA—broadly defined as any RNA
of more than 200 nucleotides that does
not appear to encode any protein—called
NEAT1, and had used my PSPC1 anti-
body to show that the lncRNA colocal-
ized with paraspeckles. When the lab
knocked down NEAT1, paraspeckles
could no longer form. I thought, here
was the paraspeckle-forming gene that
I had been searching for all these years.
Together, our labs, along with Andrew
Chess’s group at Icahn School of Medicine
at Mount Sinai in New York City, assem-
bled a narrative, published in 2009, of
how NEAT1 seeds paraspeckle formation.^4
Around the same time, two other groups—
Spector’s Cold Spring Harbor lab^5 and that
of Tetsuro Hirose at Hokkaido University
in Japan^6 —reported similar results.
We had some inkling that other groups
might be working on the same thing, but
it still came as a surprise. It was unset-
tling to suddenly find myself in a compet-
itive environment after working in rela-
tive obscurity, but the independent studies
greatly strengthened the case for NEAT1