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Helmholtz Munich | Maria-Elena Torres-Padilla

Epigenetics and Cell-Fate in Early Mammalian Development

Torres-Padilla Lab

About our Research

We combine high-resolution microscopy with single-cell genomics to study the epigenetic principles underlying cellular reprogramming in the mouse embryo.

In mammals, epigenetic reprogramming, the acquisition and loss of totipotency, and the first cell fate decision all occur within a three-day window after fertilization of the oocyte by the sperm. Molecularly, these processes are poorly understood, yet this knowledge is an essential prerequisite to uncovering principles of stem cells, chromatin biology, and thus regenerative medicine.

The chromatin in stem cells and in cells of the early embryo displays unique features compared to the chromatin of differentiated cells, including the lack of ‘conventional’ heterochromatin. We propose that the transition from a totipotent state to a differentiated one is regulated by dramatic changes in chromatin states and chromatin organisation, in particular the formation of new heterochromatin.

We study the molecular players and the sequence of events that lead to the establishment of heterochromatin de novo in the embryo. We use the repetitive elements in the mouse genome, in particular retrotransposons and the major satellite repeats found in the pericentromeric chromatin, as a model for these studies. This research has direct implications for epigenetic reprogramming and for our understanding of how a more compact chromatin configuration progressively restricts cell fate determination and cellular plasticity.

Following fertilisation, the gametes undergo epigenetic reprogramming in order to revert to a totipotent state. The mechanism through which embryonic cells subsequently acquire their fate and the role of chromatin dynamics in this process are largely unknown.

The one-cell embryo – the zygote - undergoes a series of cell divisions resulting in the formation of the blastocyst. By this time point, the first differentiation event in the mammalian embryo has occurred; segregating the outer trophectoderm, which is developmentally restricted to extra-embryonic tissues, from the inner cell mass, which comprises the first pluripotent embryonic cells. We use a variety of approaches, including single cell approaches, to determine i) the chromatin components, ii) their dynamic changes, and iii) their role in the formation of the two first lineages of the mammalian embryo. In addition, we use the data generated to model quantitative changes underlying cell fate determination. This research will have an impact on our understanding of stem cell biology and cellular plasticity.

 

Totipotent cells are unique to the early embryo and are characterised by an extraordinary potential to form the extra-embryonic tissues as well as the embryo proper. Thus, totipotent cells display larger plasticity than pluripotent cells. Histone modifications and DNA methylation patterns are dramatically remodelled during early development.

Nuclear architecture has recently emerged as a key epigenetic factor, but a role for nuclear architecture in regulating reprogramming and totipotency during early development has not been established. We are interested in understanding how the genome organisation within the nucleus is shaped during the transitions from totipotency to pluripotency, and in determining whether this organisation has a functional impact on driving cellular plasticity and cell fate. Uncovering the molecular features that establish and maintain totipotency will have major implications for our ability to manipulate cell fate and cellular state. We anticipate that this knowledge will open up the road to establishing more efficient protocols for cellular reprogramming in regenerative medicine.

The chromatin in stem cells and in cells of the early embryo displays unique features compared to the chromatin of differentiated cells, including the lack of ‘conventional’ heterochromatin. We propose that the transition from a totipotent state to a differentiated one is regulated by dramatic changes in chromatin states and chromatin organisation, in particular the formation of new heterochromatin.

We study the molecular players and the sequence of events that lead to the establishment of heterochromatin de novo in the embryo. We use the repetitive elements in the mouse genome, in particular retrotransposons and the major satellite repeats found in the pericentromeric chromatin, as a model for these studies. This research has direct implications for epigenetic reprogramming and for our understanding of how a more compact chromatin configuration progressively restricts cell fate determination and cellular plasticity.

Following fertilisation, the gametes undergo epigenetic reprogramming in order to revert to a totipotent state. The mechanism through which embryonic cells subsequently acquire their fate and the role of chromatin dynamics in this process are largely unknown.

The one-cell embryo – the zygote - undergoes a series of cell divisions resulting in the formation of the blastocyst. By this time point, the first differentiation event in the mammalian embryo has occurred; segregating the outer trophectoderm, which is developmentally restricted to extra-embryonic tissues, from the inner cell mass, which comprises the first pluripotent embryonic cells. We use a variety of approaches, including single cell approaches, to determine i) the chromatin components, ii) their dynamic changes, and iii) their role in the formation of the two first lineages of the mammalian embryo. In addition, we use the data generated to model quantitative changes underlying cell fate determination. This research will have an impact on our understanding of stem cell biology and cellular plasticity.

 

Totipotent cells are unique to the early embryo and are characterised by an extraordinary potential to form the extra-embryonic tissues as well as the embryo proper. Thus, totipotent cells display larger plasticity than pluripotent cells. Histone modifications and DNA methylation patterns are dramatically remodelled during early development.

Nuclear architecture has recently emerged as a key epigenetic factor, but a role for nuclear architecture in regulating reprogramming and totipotency during early development has not been established. We are interested in understanding how the genome organisation within the nucleus is shaped during the transitions from totipotency to pluripotency, and in determining whether this organisation has a functional impact on driving cellular plasticity and cell fate. Uncovering the molecular features that establish and maintain totipotency will have major implications for our ability to manipulate cell fate and cellular state. We anticipate that this knowledge will open up the road to establishing more efficient protocols for cellular reprogramming in regenerative medicine.

The Torres-Padilla Lab

Prof. Dr. Maria-Elena Torres-Padilla

Director of the Stem Cell Center, Director of the Institute for Epigenetics and Stem Cells, Group Leader

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Maria-Elena did her undergraduate studies at the Faculty of Sciences of the UNAM, Mexico and obtained her PhD at the Institut Pasteur in Paris in 2002. She was a postdoctoral fellow at The Gurdon Institute, University of Cambridge, UK between 2002 and 2006 and then worked as a permanent scientist with Laszlo Tora. She started her own lab at the IGBMC in Strasbourg, France, and has been leading her group since December 2008. The lab moved to the Institute of Epigenetics and Stem Cells in January 2016.

Nationality: Mexican

Contact: torres-padilla@helmholtz-muenchen.de

Dr. Jonathan Adam Burton

Deputy Head of Institute for Epigenetics and Stem Cells

Adam did his undergraduate studies at the University of Sheffield, UK, in Biochemistry. He obtained his PhD in 2010 from the MRC LMCB at University College London on the signalling role of IP6 kinases. He joined the lab in May 2010. His work has been supported by a fellowship from the Fondation pour la Recherche Médicale and he was a recipient of an EMBO short-term fellowship.
 
Research interest: Epigenetic basis of cell fate in the early embryo and heterochromatin formation.

Nationality: British

Dr. Andreas Ettinger

Head of Microscopy Core

Andreas obtained his PhD from the Max-Planck Institute of Molecular Cell Biology and the Technical University of Dresden. After working with various microscopy techniques as a postdoctoral fellow at the Max-Planck Institute and at the University of California in San Francisco, he joined the IES as head of the Microscopy Core in 2016. 

Nationality: German

Contact: andreas.ettinger@helmholtz-muenchen.de

Dr. Antoine Canat

Postdoc

Antoine did his Masters in Paris working on DNA damage response and heterochromatin. During this time he visited the lab of Rodney Rothstein at Columbia University. He obtained his Ph.D at the University of Paris under the supervision of Pierre Thérizols and Emmanuelle Fabre. His work focused on the study of heterochromatin integrity and organisation in stem cells.  Antoine joined the lab in February 2021.

Research interests: nuclear organisation and heterochromatin integrity

Nationality: French

Margarita Cespedes Barroso

Lab Manager

Margarita obtained her Bachelor in Foodchemistry and Masterdegree (Licenciatura) in  Foodtechnology  at the University of Castilla-La-Mancha (UCLM). With a Erasmus grant she was at the Saarland University where she deepened her microbiology and molecularbiology knowledge. After that, she moved to the Office of Castilla-La Mancha to the EU in Brussels. Since 2000 Margarita is in Germany working above all in the fields of proteinchemistry, molecularbiology and immunology for different companies as scientist and as technical assistant. She joined our IES- Team as lab manager in the summer 2021.

Nationality: Spanish

Yung-Li Chen

Doctoral Researcher

Yung-Li obtained both his bachelor and Master degrees in biomedical sciences at Chang Gung University, Taiwan. During his master, he focused on aberrant DNA methylation and epigenetic editing in Nasopharyngeal cancer. Yung-Li joined the lab in September 2019.

Research interest: Centromere formation and kinetochore assembly

Nationality: Taiwan

Clara Hermant

Doctoral Researcher

Clara obtained her Bachelor's in Chemistry and Biology at the University Grenoble Alpes, where she also performed her Master's in Physiology Epigenetics and Development. She first joined the lab for her final Master's work, where she focused on the analysis of the chromatin structure of specific transposable elements during development. She then joined as a Ph.D student in October 2019. 

Research interest: Transposable elements regulation in development

Nationality: Belgian

Dr. Amelie Johanna Kraus-Jaborsky

Scientific Coordinator for Epigenetics

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Amelie J. Kraus did her Master’s degree at the University of Würzburg. There, she got interested in Epigenetics and joined the Siegel's Lab for her PhD. She worked on the epigenetic gene regulation in the protozoan parasite Trypanosoma brucei. During her PhD, Amelie could gain experience in event and non-scientific project management. She joined the team in October 2019 as Scientific Coordinator for Epigenetics.

Nationality: German

Dr. Tsunetoshi Nakatani

Postdoc

Tsunetoshi obtained his Master’s degree at the Kyoto Pharmaceutical University in Japan, on the role of the P2X7 receptor in neuronal death. He performed his PhD under the supervision of Toru Nakano at Osaka University, where he studied DNA replication and its interrelationship with ectopic accumulation of 5-hydroxymethylcytosine upon Stella deletion in mouse zygotes. He joined the lab in September 2015.

Research interest: Chromatin integrity and regulation of totipotency.
Nationality: Japanese

Dr. Marlies Oomen

Postdoc

Marlies obtained her Master’s at the University of Groningen on drug innovation. She did her Ph.D in Job Dekker’s lab at UMass, where she focused on chromosome organisation, particularly during mitosis, and developed approaches to understand chromosome segregation and folding. She joined the lab in September 2021 and was awarded an EMBO fellowship for her postdoctoral work.

Research interest: Transposable elements in early mammalian development.

Nationality: Dutch

Mrinmoy Pal

Doctoral Researcher

Mrinmoy obtained his integrated Master’s degree at the Indian Institutes of Science Education and Research (IISER), Kolkata. After doing several internships at the Indian Institute of Science in Bangalore, the CSIR-IGIB in Delhi and the University of Göttingen, Mrinmoy performed his Master’s thesis in  Sanjeev Galande’s laboratory in IISER Pune, where he focused on the role of histone methyltransferases during regeneration in Hydra. Mrinmoy joined the lab in January 2019.

Research interest: Nuclear organisation in the early mouse embryo

Nationality: Indian

Dr. Federico Pecori

Postdoc

After completing his Bachelor in Biomolecular Biotechnology in Florence, Federico obtained his Master’s and Ph.D Degree at Soka University. He performed his Ph.D under the supervision of Shoko Nishihara, focusing on the functional analysis of glycosylation in murine stem cells in different pluripotent states. During his Ph.D he was awarded with the Ministry of Education, Culture, Sports, Science and Technology (MEXT) Scholarship (Top Global University Project). He joined the lab in April 2021 and was awarded a postdoctoral fellowship from the Alexander Von Humboldt Foundation.

Research interest: 3D genome organisation.

Nationality: Italian

Dr. Tamas Schauer

Senior Computational Biologist

Tamas obtained his degree in Biology at the University of Szeged, with a specialisation in molecular biology. He performed his Ph.D in Andreas Ladurner’s lab at EMBL and graduated from the LMU, where he focused on understanding cell-type specific gene expression programmes. He then performed postdoctoral training on functional genomics with Peter Becker at the BMC in the LMU, before moving on to the Bioinformatics Facility of the Collaborative Research Center ‘Chromatin Dynamics’ in the team of Tobias Straub. Tamas has performed significant research across several chromatin and transcription-related topics, as well as in genome organisation. He joined the lab as Senior Computational Biologist in January 2022.

Research interest: data analysis and integration, genomics and development of new approaches to understand cell identity from low-input methods and machine learning.

Nationality: Hungarian

Petra Hammerl

Institute Assistant

Building 90, Room 105

Recent Publications

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2021 Nature

Rajewsky, N.&deg ; Almouzni, G.&deg ; Gorski, S.A. ; Aerts, S. ; Amit, I. ; Bertero, M.G. ; Bock, C. ; Bredenoord, A.L. ; Cavalli, G. ; Chiocca, S. ; Clevers, H. ; de Strooper, B. ; Eggert, A. ; Ellenberg, J. ; Fernández, X.M. ; Figlerowicz, M. ; Gasser, S.M. ; Hubner, N. ; Kjems, J. ; Knoblich, J.A. ; Krabbe, G. ; Lichter, P. ; Linnarsson, S. ; Marine, J.C. ; Marioni, J.C. ; Marti-Renom, M.A. ; Netea, M.G. ; Nickel, D. ; Nollmann, M. ; Novak, H.R. ; Parkinson, H. ; Piccolo, S. ; Pinheiro, I. ; Pombo, A. ; Popp, C. ; Reik, W. ; Roman-Roman, S. ; Rosenstiel, P. ; Schultze, J.L. ; Stegle, O. ; Tanay, A. ; Testa, G. ; Thanos, D. ; Theis, F.J. ; Torres-Padilla, M.E. ; Valencia, A. ; Vallot, C. ; van Oudenaarden, A. ; Vidal, M. ; Voet, T. ; LifeTime Community (Schiller, H. B. ; Ziegler, A.-G.)

Publisher Correction: LifeTime and improving European healthcare through cell-based interceptive medicine (Nature, (2020), 587, 7834, (377-386), 10.1038/s41586-020-2715-9).

2021 Scientific Article in Metabolites

Huang, J. ; Covic, M. ; Huth, C. ; Rommel, M. ; Adam, J. ; Zukunft, S. ; Prehn, C. ; Wang, L. ; Nano, J. ; Scheerer, M.F. ; Neschen, S. ; Kastenmüller, G. ; Gieger, C. ; Laxy, M. ; Schliess, F. ; Adamski, J. ; Suhre, K. ; Hrabě de Angelis, M. ; Peters, A. ; Wang-Sattler, R.

Validation of candidate phospholipid biomarkers of chronic kidney disease in hyperglycemic individuals and their organ-specific exploration in leptin receptor-deficient db/db mouse.