CSHL Scientists Discover a new Way in which Epigenetic Information is Inherited

Hereditary information flows from parents to offspring not just through DNA but also through the millions of proteins and other molecules that cling to it. These modifications of DNA, known as “epigenetic marks,” act both as a switch and a dial – they can determine which genes should be turned on or off, and how much message an “on” gene should produce.

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.

In a paper 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.

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.