CSHL scientists discover a new way in which epigenetic information is inherited

One way in which epigenetic information is known to
be passed from parent to offspring is through the pattern of chemical
"caps" added onto certain "letters" of the DNA sequence, ensuring the
sequence is "silenced." How these DNA capping patterns, which are
inherited, are precisely set is not yet known. But in some cases,
enzymes that add these caps are guided to DNA by small RNA molecules.
These guides themselves do not carry hereditary information, but they
do mark the spots where DNA is to be modified.

A team of
scientists at Cold Spring Harbor Laboratory (CSHL) led by Professor
Gregory J. Hannon, Ph.D., has now discovered that a class of small RNAs
does carry epigenetic information and in fact passes on the trait of
fertility from mother to offspring in fruit flies.

A new mechanism of inheritance

In
a paper to be published on Nov 27th in Science, the CSHL team reports
that maternal small RNAs called Piwi-interacting RNAs (piRNAs) that are
deposited into fruit fly embryos "silence" DNA sequences that induce
sterility, thus ensuring the fertility of the progeny. "This is a whole
new way in which heredity can be transmitted," says Professor Hannon,
who is a pioneer in small RNA research. "With this finding we’ve
effectively doubled the number of mechanisms by which epigenetic
information is known to be inherited."

The piRNAs are found only
in cells of sex organs and partner up with proteins called Piwi to
suppress the activity of mobile DNA sequences called transposons.
Discovered half a century ago by CSHL scientist and Nobel laureate
Barbara McClintock, Ph.D., transposons jump around the genome,
inserting themselves into genes and causing mutations. Such genetic
havoc is thought to underlie many diseases, including cancer.

A
high rate of mutations also disturbs gametogenesis – the process of
creating viable sex cells – and can result in sterility. Piwi proteins
and piRNAs form something akin to an immune system in sex cells that
guards against transposon-inflicted genome damage.

Solving the fruit fly fertility puzzle

The
CSHL team wondered whether piRNAs were also the key to a long-standing
conundrum about fertility in fruit flies. When lab-bred female flies
are bred with male flies caught in the wild, their progeny are sterile
or unable to produce offspring — a phenomenon called hybrid
dysgenesis. But the genetically identical offspring of wild-caught
female flies and lab-bred males are fertile. The genetic difference
between the lab-bred and wild flies is a single transposon, which is
absent in lab strains.

In hybrid dysgenesis, the transmission of
the transposon by a parent induces sterility in the offspring unless
the offspring also inherits a factor that suppresses the transposon and
maintains fertility. Since the phenomenon had only been seen when the
transposon-transmitting parent was male, the suppressing factor was
thought to be maternally transmitted. But it was never identified.

Hannon’s
team has now found that the stockpile of maternally derived proteins,
RNA, and nourishing raw material in developing fruit fly oocytes, or
egg cells, also includes piRNAs. And these maternally deposited piRNAs
prove to be essential for mounting a silencing response against
transposons.

Inheritance via small RNAs

Hannon likens
this protection to that afforded by the adaptive immune system which
protects against pathogens like bacteria and viruses. "We’ve evolved
ways to transmit immunity from mother to child via the secretion of
antibodies," he says, referring to the proteins that can cross the
placenta and protect the fetus or get passed on to an infant via
breast-milk. "We now have a way in which immunity (against sterility)
is passed on from mother to child, in flies but possibly other
organisms also, via small RNAs."

In contrast to short-lived
adaptive immunity, however, this small RNA-driven immunity has a long
reach. The team’s experiments show that the effect on fertility doesn’t
just impact the child alone, but also the next generation. Because the
trait – fertility – is controlled or encoded in the RNA, "you’re
passing on a trait that’s essentially not only controlling an event
that happens in the organism’s adulthood, but is also propagated to the
progeny of that organism," explains Hannon.

The impact of environment

The
ability of the mother to transmit epigenetic information can be altered
by the environment that she finds herself in. Other researchers have
found that raising the temperature in which female flies are reared
raises the proportion of fertile progeny.

To the CSHL team, this
suggests that "the experience of the mother translates into a dominant
effect on the progeny." The group’s data suggest that one way that the
mother’s experience might get communicated to the child is through
variations in the populations of small RNAs that get deposited in the
oocytes.

Now that one trait has been discovered to be driven by
maternally inherited piRNA, Hannon is eager to know if the spectrum of
information that’s transmitted in this way can be broadened to cover
other cellular processes. And of course, it also remains to be seen
whether this mechanism of epigenetic inheritance is found in organisms
besides fruit flies. "Small RNAs are probably deposited in oocytes of
every animal," he hypothesizes.

Source : Cold Spring Harbor Laboratory