Maria-Elena Torres-Padilla has been awarded with a large grant under the NIH 4D Nucleome program

The Torres-Padilla lab of the Helmholtz Zentrum München has joined Phase II of the NIH Common Fund’s 4D Nucleome (4DN) program and receives around 1.2 Million € over 3.5 years to uncover how nuclear organization is first established after fertilization in mammals. On December 2nd, Prof. Maria-Elena Torres-Padilla, Director of the Institute for Epigenetics and Stem Cells, presented the funded project and outlined how they plan to benefit the 4DN community during the 2020 4DN Phase II Kick-off Meeting.

Prof. Maria-Elena Torres-Padilla, Project Leader

Dr. Adam Burton, Senior Scientist

Logo of the 4D Nucleome Program

The 4-Dimensional Nucleome (4DN) is a research program funded by the Common Fund at the National Institutes of Health in the United States. The program was initiated in 2015 with the goal to provide answers to how our genetic material is organized within the nucleus in three dimensions, how this organization changes over time (4th dimension) and if it impacts human health and disease.

The program is dedicated to the development of new tools that enable the study of nuclear architecture dynamics, its role for cell function and how it differs in healthy and diseased cells. The key intention of the program is to provide valuable resources accessible for everyone to promote continuing research of the three-dimensional nuclear organization in space and time beyond the initiative. In the first phase (2015-2020) the program made major advances in pioneering innovative technologies, providing resources, and publishing data that are accessible for everyone. Phase II of the program has recently been initiated and comprises six cross-topic initiatives leveraging the knowledge gained from Phase I to now address the role of the nuclear organization in health and disease.

Alongside Prof. Ana Pombo from the Max-Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association, and Prof. Mario Nicodemi, MDC guest scientist, the research team around Prof. Maria-Elena Torres-Padilla and Dr. Adam Burton, the Deputy Director of the Institute, is one out of three labs in Europe that has joined the 4DN program for Phase II. Their project has been awarded (Award number: U01DK127391) under the initiative “Real-Time Chromatin Dynamics and Function” and they receive around 1.2 Million € for 4 years to study the genomic structures that lay the foundation of nuclear architecture using the mouse embryo as model organism and to determine their role for development and cell identity.

The dynamics of 3D-genome organization at the onset of mammalian development can provide valuable insights into the hierarchy of nuclear architecture establishment.

Development of a mammal starts with fertilization of the oocyte by the sperm. Both are highly differentiated and specialized cell types. On the other hand, the resulting zygote has the highest degree of cellular plasticity and potency and can differentiate into all cell types and tissues of an organism. This capacity is known as ‘totipotency’. The formation of the zygote requires an extensive process of chromatin remodeling in the embryo and only if the epigenetic pattern of the gametes has been successfully reprogrammed, totipotency can emerge. In particular, the 3D genome organization has to be established de novo in the first few cell division cycles of the preimplantation embryo, laying the foundation for the genome organization in all the cells of our body. This process is highly dynamic and includes major genomic rearrangements in only a short time frame after fertilization. Previous work of the Torres-Padilla lab has already shown that the formation of genome-lamina interactions is likely the first scaffold of nuclear architecture in the early mouse embryo.

Still, very little is known about how mammalian genomes are arranged over time in the nuclear space, in particular at the onset of mammalian development. As part of the 4DN community, the team around Maria-Elena and Adam aims to change this. “The early mouse embryo is a fantastic model system to study developmental processes in vivo.”, said Adam. “It can be cultivated and manipulated in a petri dish until the blastocyst stage. But the major advantage is that it is amenable to live imaging. Altogether, very promising prerequisites to study nuclear organization dynamics in a real-time and in vivo context.” Now through the support of NIH and the 4DN community, they will develop new imaging tools to visualize the fundamental pillars and real-time dynamics of nuclear architecture during embryonic preimplantation development.

‘Accessible research and collaborative science’ – The 4D Nucleome at a glance

The virtual kick off meeting of 4DN Phase II, which took place in the first week of December, provided a great opportunity for the members of the 4DN community to get to know the organizational regulations, the other projects and to identify potential collaborators. It was organized by the 4D Nucleome Organizational Hub as a virtual meeting streamed from San Diego. Thus, it was already 9 pm in Munich, when Maria-Elena introduced the project to the 4DN members. “I have to admit that I prefer the jetlag over staying up late. But in these times, this is how it should be done.”, she said with a smile. “It is a great honor and acknowledgement of our work that we are now part of this excellent research program alongside such outstanding researchers. I am looking forward to the discussions, meetings and collaborations over the next years.” The 4DN program strongly emphasizes collaboration among the members and has elaborated many strategies to make the findings accessible for everyone. For example, it is obligatory to upload a paper that is submitted for peer-review to a preprint server. “I really appreciate their ‘science has no borders’ approach`. Science is knowledge generation and knowledge is for everyone”, Maria-Elena adds. “An exciting time has started now for my lab, hopefully with many fruitful collaborations. If the science is not convincing enough, we still have the best beer to offer.”

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