Epigenetics for all

If you would like to get to know the researchers of our community, check out the interviews.

The PhD student Jessica Pellegrino talks about her project at the IFE

 

 

 

Jessica Pellegrino is a PhD student in Robert Schneider’s team at the Institute of Functional Epigenetics. Here she tells us more about her research and what it’s like to work at Helmholtz Zentrum München.

Can you explain the question you are addressing and the main importance of your study?

Jessica: My research focuses on whether a cell, when challenged with a stimulus, can remember that it was challenged and thereby adapt its response when it is challenged again. Simply put, I take away glucose from a cell in culture and it has a response that can be measured by changes in gene expression. The cell is then allowed to recover by giving it back glucose and then we take away the glucose a second time. The cell shows a gene expression response that suggests it “remembers” this challenge and therefor can adapt to it. The main goal of my project it to study this “transcriptional memory” and to determine how it works.

What is the biggest challenge in your project?

Jessica: The most challenging aspect of my project was establishing the proper system to study this transcriptional memory. I spent many months optimizing the system and timing of the experiments. Though this was very painstaking work at the beginning, it paid off once I began my experiments and I was confident I was looking at the correct time points to answer my questions.
 
What attracted you to do your PhD in the Schneider lab and what is your favourite thing about the Helmholtz research environment?

Jessica: The choice to do my PhD in the Schneider lab was a combination of my interest in the study of epigenetics and the ability to work on an independent project but still receiving guidance from Dr. Schneider and my lab mates.

The Helmholtz research environment is very diverse in respect to both the research subjects and the people who work on them. I enjoy learning about the work done at Helmholtz, even if it is not directly related to the field I am in and that inspires me to think about science in different ways.

Visit the lab webpage to find out more about work in the Schneider team

Diego Rodriguez-Terrones - PhD student in the Torres-Padilla Lab - tells us more about cell potency

 

Diego Rodriguez-Terrones is a PhD student in the Torres-Padilla group at the Institute of Epigenetics and Stem Cells. He recently co-first authored a paper in Nature Genetics looking at the mechanisms behind changes in cell potency. Here he tells us more about the study and his research motivations.

In your recent publication you identified a mechanism through which embryonic stem cells in culture can change to cells resembling those found in the 2 cell embryo. Could you explain the importance of this transition and the main take home message of your study?

Diego: In the lab we aim to understand the molecular basis of totipotency, which is the capacity of a single cell to give rise to an entire organism. For example, in the mouse, the one cell of the 1-cell embryo and each of the two cells from the 2-cell embryo are the only three totipotent cells that occur during development. What this essentially means is that, if you let a 1-cell embryo develop to term, you will get one mouse, and if you split the 2 cells from the 2-cell embryo and let them develop independently, you will get two twin mice. This unique capacity of these three cells does not occur later in development and we are interested in understanding why. Unlike pluripotency — for which the field has accumulated an extensive understanding of its regulatory foundations and has even been able to induce pluripotent cells in vitro for over a decade — we have few insights into the regulation of totipotency and the molecular factors that confer totipotent cells their exceptional cellular potency.

A few years ago, another group reported the existence of a small subpopulation of mouse embryonic stem cells that recapitulates some features of totipotent cells, and because of their resemblance in some aspects to the cells of the 2-cell embryo, they were named 2-cell-like cells. In our recent publication, Xavier Gaume, a post-doc in our team, and I aimed to clarify the origin of this peculiar cell population and the molecular determinants that regulate their emergence. Using an ensemble of single-cell techniques, we managed to identify a set of intermediate cellular states that mouse embryonic stem cells undergo when transitioning to the 2-cell-like state. This information helped us to understand how the 2-cell-like population typically emerges in vitro, and permitted us to observe it live using time-lapse microscopy. Additionally, we also undertook a screening to identify regulators of the distinct steps of the transition and managed to identify several protein complexes that restrict entry into the 2-cell-like state.

What fascinates you most about the question you are addressing?

Diego: Well, I think it’s beautiful to discern the diversity of regulatory states that coexist in embryonic stem cell cultures. In our study we have identified at least three distinct populations based on their gene expression programs and then used this information to track the transitions between the different states. I really like that! It’s like having Waddington’s landscape  on a dish, and the ball sometimes kind of gets back to the top of the hill by itself!

What was the biggest challenge in your project?

Diego: The biggest challenge was probably the very rare nature of the 2-cell-like population, which prohibited us from employing many techniques that require high cell numbers. This actually turned out to be a strength, however, since it forced us to employ single cell techniques which permitted us to observe phenomena that would not be possible to discern otherwise.

What is your favourite thing about the research environment?
 
Diego: It’s certainly the confluence of so many teams working on epigenetics and stem cells in a single community. You can certainly count on someone working with the technique or the aspect that you have in mind, and who you can consult if needed. It’s also really good that there are also many, many seminars happening all the time, perhaps even more than you have time to attend to!

More on Diego's publication: Rodriguez-Terrones, Gaume et al., (2018) Nature Genetics and Helmholtz Zentrum Press Release

The PhD student Lea Schuh from the IFE and ICB shares her experience about her time abroad

Lea, thanks for taking the time to talk to us.  You are currently taking part in a research project as part of the International Partnership with UPenn Epigenetics Institute. Could you tell us a bit about the project you are working on and what motivated you to participate in the programme?

Lea: Thank you for giving me the opportunity to share my experiences! I joined an ongoing project where we are trying to understand the origins of resistance in melanoma, a common form of cancer. Only around 1:1000 cells may acquire resistance – but these suffice to provoke relapse in almost 80% of the patients. 
The Raj lab at the University of Pennsylvania has so far been able to propose a two-step mechanism leading to stable resistance: 1) before drug application, cells may reversibly transition from a non-resistant to a transient-resistant state 2) after drug application, only cells previously in the transient-resistant state may survive and are then subjected to epigenetic reprogramming completing the transformation to stable resistance. 
By computational simulations, I am trying to identify the role of stochasticity within a particular gene network and its influence on the formation of rare-cell behavior. Specifically, I am trying to understand what kind of network architectures and network properties are essential to elicit rare-cell behaviors. We hope that this might lead to a better understanding of how transient-resistant cells are formed in the first place.  

Personally, participating in this exchange has been about broadening my horizon – educationally as well as personally – and getting out of my comfort zone. This opportunity enables me to gain experience in an exceptional lab which elegantly combines cutting-edge computational and experimental biology, to work with a group of excellent researchers from very diverse educational backgrounds and origins, and to explore a new country with its language, culture, and people. 

What fascinates you most about your project?

Lea: So far, this project has revealed the general mechanisms leading to resistance formation in melanoma – simultaneously, it has triggered a whole set of new questions about the more detailed biological and genetic events underlying, controlling and driving these mechanisms. What fascinates me is the scope of these questions and the diverse research areas addressed by them. It highlights and promotes the necessity of interdisciplinary research and allows for a wide range of experimental and theoretical approaches.
 
What is your favourite thing about the research environment?

Lea: Honestly: curiosity! The research environment promotes curiosity, open-mindedness and innovation in terms to pursue the former. It allows for and grows with unforeseen developments and pushes each and every single person to keep on questioning and coming up with new and exciting hypotheses. 

What do you like to do in your spare time?

Lea: I love to go running which also is a great way of exploring Philadelphia – the pedestrian-friendliest city in the US! Apart from that I enjoy visiting museums, reading and travelling. I am really excited to go to Washington DC, New York City, Chicago and Boston during my stay here.

Nilay Shah talks about what he learnt during his PhD studies

Nilay Shah recently completed his PhD in Dirk Eick's lab.  Here he explains his recent publication in Molecular Cell, looking at the role of RNA Polymerase II in transcription termination, and some things he learnt during his PhD studies.

In your recent publication you discovered the role of RNA polymerase II in the regulation of transcription termination.  What makes this research so important and what was the biggest surprise for you during this study?

Nilay: In our study we described how the C-terminal domain (CTD) of RNA Pol II contributes in the tight regulation of termination processes for sense and antisense transcripts. This work is very important, as it will pave the way to better understand and decipher the detailed mechanism of Pol II termination, a process that still remains poorly understood.

The biggest surprise for me was the extent of the termination defect phenotype that we observed in our Pol II mutant. The effect was massive spanning up to several hundred kbs.
 
What keeps you motivated working in the lab?

Nilay: It is a lot easier to remain motivated when things are working well during the project. However, it gets difficult when things do not work according to the plan. 
I am fortunate enough to have a bunch of fantastic people around me, including my colleagues and friends who helped me remain motivated. 
 
You recently finished your PhD, what’s the most important thing that you learnt during your PhD?

Nilay: The most important thing I learnt from my PhD was the art of perseverance. At times, it was important to remain patient and keep working hard. 

More on Nilay's publication: Shah, Maqbool et al., (2018) Molecular Cell and Helmholtz Zentrum Press Release

Alex Wolf talks about his research and why it fascinates him

Dr. Alex Wolf is a postdoctoral fellow in the Theis Lab of the Institute of Computational Biology.

In your recent publication you developed a computational approach for the analysis of single cell gene expression data. What makes this research so important?

Alex: By reporting distributions over single cells, single-cell data provides a whole different level of insight compared to bulk data, which only report tissue averages. We all know that the average income of a country doesn't tell us much about the well-being of its citizens: a decently appearing average could hide the fact that there are a lot of poor people with a single billionaire. Similarly, many diseases are extremely heterogeneous in terms of their cellular composition. By contrast, different individual humans become more similar at the single-cell level, when ignoring the cellular composition. That is, many differences between humans are due to their different cellular compositions. This is also why a project like the Human Cell Atlas makes sense: the cells of very few individuals can serve as a generic reference for the basic building blocks of life for all humans.

Scanpy is a toolbox providing the canonical data analysis methods for gene expression data at the scale of millions of cells. Hence, it is able to deal with the amount of data generated in the Human Cell Atlas and can be used for jointly analyzing - aggregating - published studies.

What is the biggest challenge in your work?

Alex: Understanding fundamental questions that biologists ask and finding efficient ways for writing tools that helps answering these: the challenge is to balance the strive for beautiful concepts and code with "making things work" and the need of addressing biological details. Being good at guessing what can be computed and what cannot.

What motivates you to pursue this particular research line?

Alex: It is a highly dynamic, lively research field with potentially a lot of applied and fundamental impact.