Mar 8, 2016

Author: Jovana Drinjakovic

You’d be forgiven if you mistook Henry Krause’s data for art. Using molecular tricks, Krause turns the humble-looking fruit fly embryos into striking patterns of stripes, dots, and swirls that will forever change how you see flies. But more importantly, these patterns also reveal the extraordinary degree of control cells have evolved to ensure seamless execution of their genetic programs.

The genes’ sequences are copied into transient RNA molecules – these carry instructions for making proteins, which in turn build our cells and bodies. Now Donnelly Centre investigator Dr. Henry Krause and his team reveal an astounding degree to which RNA molecules are strategically positioned within cells and tissues during development, to make sure that the right proteins are made at the right place and time. But this is also true for the elusive family of the long non-coding RNAs (lncRNAs), which do not code for proteins, offering a rare glimpse into their biological significance.

As a comprehensive atlas of RNA’s whereabouts in cells and tissues, the study, out March 1 in Genes and Development, will benefit researchers worldwide who explore genetic and molecular processes.

The work builds on the team’s previous breakthrough, which found that 70% of protein-coding RNAs were distributed into hundreds of distinct patterns in early embryos prior to being translated into proteins. The finding astonished the scientific world, upending the previously held belief that most proteins are shuffled to their correct destinations after being made. Krause’s data suggested that it is the RNA that gets moved around, setting the stage for the protein to be synthesized at the correct location.

But many believed that such extensive control of RNA distribution was unique to flies, called for by their peculiar early development that proceeds without cell division. Critics argued that RNA localization evolved as a way of delineating different parts of the embryo in the absence of internal cell boundaries, which only appear about three hours into development.

Krause and his colleagues addressed these questions by looking at un unprecedented number of RNA molecules – more than 8,000, or half of all protein-coding RNAs in the fly - and across different developmental stages, including those that occur similarly in both flies and vertebrates. And the results are a sweeping validation of the earlier conclusion. Essentially all examined RNAs existed in distinct spatial distributions in cells at some point during development.

A glimpse into the breadth of RNA (in blue) distributions within cells. Nuclei are in red

A glimpse into the breadth of RNA (in blue) distributions within cells. Nuclei are in red

The data establish that RNA targeting in cells is the norm, not the exception, and it is likely to be as pervasive in vertebrates, including humans, as it is in flies. So why does this matter? It is becoming increasingly clear that mistakes in RNA distribution can lead to disease, including neurological disorders and cancer. Understanding the mechanisms behind this process might help develop new treatments.

But the immediate far-reaching application of Krause’s work is that it will advance further research and help scientists understand the roles of molecules they do not know much about. This is especially the case for the lncRNAs – a baffling family of RNA molecules whose prevalence in the genome grows with evolutionary complexity and might even be the force behind it. Despite outnumbering protein coding messages by at least four to one, their role in cells remains a mystery.

“If lncRNAs are non-functional, you would assume that they are randomly and similarly localized in cells, but all of the lncRNAs examined in this study have exquisite, unique patterns. I’ve never seen nature doing things for nothing and the way these lncRNAs are arranged in a cell suggests they are doing something important there,” says Krause who is also a professor in the Department of Molecular Genetics.

Even among the protein-coding genes and RNAs, scientists have a firm handle on only a small subset. Krause’s data, combined with other available databases, has the power to change this by advancing future discovery.

“The database that we’ve put together should allow a lot of researchers to learn a lot more about not just the genes and processes that they are interested in, but also about other genes that were not known to be involved in those processes. It should accelerate a number of different initiatives around the world, and not just for fly research, but for people working on related genes in other organisms, including humans,” says Krause.