The European Research Council (ERC) has awarded Julius Brennecke, Senior Scientist at IMBA, an Advanced Grant for his project on transposon-host coevolution. This is already the third ERC Grant for Brennecke, following his ERC Starting Grant and Consolidator Grant. The ERC Advanced Grant is the most highly endowed European research grant. The funded project is the next step in the Brennecke Lab’s long-term pursuit to unravel the continuously evolving cellular mechanisms that protect the genome from selfish genetic elements.
Transposable Elements Promote Biological Innovation
Transposable elements (TEs) are selfish genetic sequences able to invade the genome of their hosts and replicate within it. These "genome parasites” exploit the cellular resources of their hosts for their own propagation. However, by inserting into and excising from the host genome, transposons often compromise the integrity of the host’s genome. In response to this threat, host cells have evolved defense strategies to detect and silence transposons. However, TEs are highly adaptable and evolve new ways to escape the cell’s tight control. In this biological conflict, both transposons and genome defense systems co-evolve, trying to stay one step ahead of the other. This arms race has led to significant biological innovations, giving rise to cellular processes like DNA methylation and RNA interference.
Flipping the Script: A New Angle on an Old Conflict
The group of Julius Brennecke, senior scientist at IMBA since 2014, has spent the last fourteen years studying TE-host coevolution. “In the last decade, my group combined genetics, molecular biology and biochemistry techniques to study how the Drosophila host deals with TEs,” Brennecke explains. The Brennecke group contributed significantly to identifying and dissecting the PIWI-interacting RNA (piRNA) pathway, the main animal defense system responsible for silencing transposons. “About three years ago, we also started to look at the other side of this conflict, trying to understand how TEs evolve to ensure their survival and replication,” Brennecke adds. Last year, the Brennecke group described how retrovirus-like TEs in the fruit fly Drosophila melanogaster evolved distinct expression patterns that maximize their ability to infect germline cells from surrounding somatic cells.
Now, the group wants to understand how endogenous retroviruses diversified their infection strategies and regulatory sequences to escape the genome defense mechanisms. In addition, the Brennecke team seeks to understand how the piRNA pathway in turn exploits an Achilles’ heel in transposon sequences to stay ahead in the conflict.
Infiltrating the Lineage
The Brennecke Lab studies how a specific class of TEs, called retrotransposons, gained the ability to infect other cells and became retroviruses. In Drosophila, retroviruses adapted their infectivity strategies to different cell types in the ovarian soma to ensure their survival. From the soma, they can then infect the germline cells (eggs) and thereby target the immortal germline genome.
Once TEs had learned to infect other cell types, they needed to adapt their expression patterns to maximize their survival. “For a TE to stay in the genome, it must be active and manage to sufficiently escape all control systems and replicate in the host genome. The TE needs to be expressed at the right time and take advantage of the host’s cell biology to go into the nucleus and insert into the host DNA,” Brennecke explains. The TEs that successfully adapt to be expressed in a cell are preserved in the genome. “We can look at this as a fossil record in the genome. The sequences we find in the host genome allow us to look back in history and figure out which strategies the successful TEs used,” Brennecke adds.
In collaboration with the lab of Alex Stark at the Research Institute of Molecular Pathology (IMP), also at the Vienna BioCenter, the Brennecke Lab will combine the STARR-seq technology and machine learning-based neural networks to map the gene regulatory network of different cell types in the Drosophila gonads. This map will serve as a basis for identifying how TEs adapt their expression patterns to different cell types. “This kind of research was unfeasible before,” Brennecke explains. “Now we know enough about the host and how to modify it, and we have access to new technologies that allow us to study TE biology at another leveI.”
Unraveling the Achilles' Heel of Transposable Elements
Despite the remarkable adaptability of TEs, the host genome defense mechanisms are equally flexible. However, how genome defense mechanisms are able to continuously adapt to recognize and silence rapidly evolving TEs is, so far, poorly understood. As Brennecke puts it: “If transposons change all the time, how does the host keep track?” The Brennecke Lab will investigate whether a specific feature in TE sequence composition could be used by the host’s defense mechanisms to easily recognize TEs and build new defenses against them. “We will try to understand this system at the molecular level, but also ask whether in a transposon invasion, when the host has to adapt, the genome defense can exploit an Achilles’ heel in the TE sequence,” Brennecke explains.
About the ERC
The European Research Council, set up by the European Union in 2007, is the premier European funding mechanism for excellent frontier research. The ERC’s mission is to facilitate the highest quality of research across all fields in Europe through competitive funding. The ERC offers four core grant schemes: Starting Grants, Consolidator Grants, Advanced Grants and Synergy Grants.
“The ERC granting system has reshaped basic science funding in Europe and strengthened the European basic science landscape,” Brennecke says. “In addition, obtaining ERC funding serves as a credibility stamp on the quality of the research performed. This, together with the economic stability provided, will improve our lab’s visibility and recognition and help us recruit talented graduate students and postdocs in the future”.
ERC Advanced Grants provide long-term funding for established, leading principal investigators who want to pursue a ground-breaking, high-risk project. ERC Advanced Grants provide funding of up to 2.5 million Euro for a period of 5 years to support personnel and research costs of the funded project. Julius Brennecke’s current ERC Advanced Grant is the twenty-second ERC grant awarded to faculty members at IMBA. Julius Brennecke has already received an ERC Starting Grant as well as an ERC Consolidator Grant.