Diego Rodriguez-Terrones

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

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