ERC Starting Grant: Interview with Stephan Hamperl

Stephan Hamperl received an ERC Starting Grant in 2019. He is a group leader at the Institute of Epigenetics and Stem Cells, Helmholtz Zentrum München. During the funding period from 2020 to 2025, he will receive roughly 1.5 million Euros from the European Research Council. We talked to him to hear more about the Grant and his ambitions in his scientific field.

© Helmholtz Zentrum München

1. What was your first thought when you heard that you received the ERC Starting Grant?

This was a very exciting day! After the ERC interview in Brussels, I knew that the decision should be communicated by the end of July. Thus, I was quite nervous everyday opening my mailbox during this week. Finally, when the email arrived, I remember quite well my inner resistance not to open and read the message. In the end, my curiosity won and I was just really happy and relieved that it worked out in the end. 

2. Please describe your project to us.

Many fundamental processes occur on our chromosomes, two of which are transcription of genes and replication to copy our DNA strands. These molecular machines traverse our genome simultaneously with different rates and often in opposing directions. Maybe not so surprising, they can sometimes “crash” into each other and collide, leading to transcription-replication conflicts. In this project, we aim to understand how cells regulate gene expression with the DNA replication program and therefore prevent collisions between the transcription and replication machineries. We also aim to identify hotspots in our genome where such conflicts occur and identify the molecular players and chromatin-based mechanisms that are involved to resolve and overcome them.

3. How did you get the idea for this project and why does this research-question fascinate you?

We started working on this problem during my postdoctoral research at Stanford University. A major challenge to study such conflicts is that they are rare events and occur transiently at random positions on the genome so that it is difficult to accurately detect and monitor them. To overcome this, we established a model system where we can induce transcription-replication conflicts on specific model loci using human cells grown in culture. In this project, we plan to use this system to address the molecular details of these collisions but also develop new systems to detect and analyze conflicts on the endogenous genome with single-cell and single-molecule based assays.
I’m fascinated by the flexibility and versatility of our chromosomes – highly compacted to fit in our nucleus but at the same time highly dynamic to allow access to all these different cellular machineries involved in DNA repair, DNA replication, transcription, chromosome organization and many more. How do cells regulate and coordinate all this traffic on our genome so that they don’t interfere with each other? Finding an answer to this question is a major aim of my research team.

4. How will the scientific world benefit from your research in this field?

The way by which such “accidents” are avoided and resolved in our cells is unknown. If we shed light on the basic mechanism and molecular consequences of such conflicts, we may be able to design new strategies and improve “conflict resolution” at these regions in the genome. This could guide future therapeutic efforts relevant to cancer and other human diseases.

5. And for the non-scientists amongst us: In a nutshell, what is your research question?

Simply speaking, you can think about these molecular machines as cars and the DNA strand as a highway (In real life, the machines are enzymes.) These cars could meet in different orientations (head-on versus co-directional) but also in different functional states (e.g. at slow or fast speed). Would the results of these different types of conflicts be the same? Based on what’s happening on our highways, you can already guess that the outcome is quite different and the same is true in our cells. In this project, we hope to define the outcome and functional consequences of different accidents on our cellular “highways”.