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Small But Mighty

There is a long-held tradition in fruitfly research for silly gene nomenclature. For example, take the inspiration from mutations that affect fruit fly testes. The so-called “defenders of DNA,” the Piwi (for P-element induced wimpy testis) family of proteins, got its incongruous name from the researcher who discovered the gene in honor of the mutant fruitfly with malformed testes.

 All joking aside, the Piwi-interacting RNAs play an important role in human development.  They’re small molecules that comprise a class of non-coding RNAs that form complexes with Piwi proteins, which have been linked to silencing elements of the genome so that sperm and egg cells can mature properly.

These elements are sequences of DNA called transposons (some are leftovers from older viral infections) that can cause genetic damage that leads to disease – such as hemophilia, Duchenne muscular dystrophy, and some cancers. Piwi proteins and piRNAs protect the genomes of sperm and egg cells from damage from these transposons.

What non-protein-coding RNAs do is still relatively unknown and is currently under intense investigation by hundreds of research groups around the world. However, given how pervasively the human genome is transcribed, researchers believe that RNA likely plays an important role in normal human development and response to disease, but to a large extent non-protein-coding RNA is still part of the biological “dark matter.”

The piRNAs belong to this dark portion of the genome – and are part of a relatively new field, having been first described in 2006.

A new study, recently published in Nature and led by Anastasios Vourekas, PhD, a research associate in the lab of Zissimos Mourelatos, MD, a professor of Pathology and Laboratory Medicine, examined the role of Piwi-interacting RNAs and the Piwi protein called Aubergine during the development of  immature cells into mature egg and sperm cells and how they keep them out of harm’s way from transposons.

The analysis was run by co-author Panagiotis Alexiou, with Nicholas Vrettos and Manolis Maragkakis also contributing. The Mourelatos team reported an unexpected role for Aubergine-piRNA complexes in egg cells, which goes beyond transposon control and uses the sequence of building blocks called nucleotides like a “molecular Velcro.”

Researchers have known that in fruitflies and other animals, egg and sperm development in the embryo is driven by messenger RNAs (mRNAs) from the mother. It is also known that proteins that assemble into the complexes concentrate in a specialized compartment called the germ plasm at the posterior of the egg cell. Piwi-interacting RNAs, especially those associated with Aubergine, are shuttled to the germ plasm to silence transposons in the developing egg cell, after it has been fertilized.

The Mourelatos team found that piRNAs can bind maternal mRNAs by nucleotide-to-nucleotide matching. This hunch has long been suspected and actively pursued by investigators, but surprisingly the Penn team found that the match is made in a random fashion. They also found that the piRNAs work with scaffold proteins in the germ plasm to create an adhesive trap -- the molecular Velcro -- that captures mRNAs at a specific stage of egg-cell development.

Messenger RNAs from egg cells are preferentially trapped because they are physically longer and more abundant and so can physically make more contacts with piRNAs compared to other types of mRNAs in the cell. This function of the Aubergine-piRNA complexes is additional to, and distinct from, transposon silencing. The specification in this process may help to ensure that most transposons are silenced.

“We are now turning our attention to ask if piRNAs and Piwi proteins organize into a similar mRNA trap during sperm formation,” Vourekas said.

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