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Helmholtz Munich | Eva Hörmanseder

Maintaining and Reprogramming Cell Fates

Hörmanseder Lab

About our Research

We combine somatic cell nuclear transfer to Xenopus eggs with innovative multi-omics to study how a cell can remember its identity in order to erase its memory.

 

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 uncover principles of stem cells, chromatin biology, and thus regenerative medicine.

During development, the totipotent zygote undergoes multiple rounds of cell division and differentiation. The arising daughter cells commit more and more to a certain cell lineage losing cellular plasticity until they reach their final cell fates, e.g. becoming a skin cell. Each differentiation step is accompanied by specific changes in gene expression to establish a stable cell state — a ‘memory’ of cell fate is acquired. This cell-fate memory is highly protected and cannot be easily changed in nature. However, in the petri dish, vertebrate eggs have the remarkable ability to reprogram cell fates when the nucleus of a somatic cell is transferred to an enucleated egg. The so-generated nuclear transfer embryo can erase the cellular memory of the previous cell identity, allowing the establishment of totipotency, and can so give rise to all cell types of the body. That has a fundamental impact on regenerative medicine.
We aim to unravel the epigenetic mechanisms that stabilize differentiated cell fates and inhibit the reprogramming of cell fates in order to achieve a fast, efficient, and complete switch in cell fate directly or within a few cell cycles.

One of the most fascinating aspects of life is that the fertilized egg (zygote) can form a full new organism. In animals, development starts with the fertilization of the oocyte by the sperm, two highly differentiated cells. The resulting cell, the zygote can form a full new organism by itself. We call this capacity ‘totipotency’ which is the highest degree of cellular plasticity. Totipotency occurs naturally for a short time window at the onset of vertebrate development. The generation of totipotent cells in the laboratory holds enormous promises for regenerative medicine since it would enable replacing ‘sick’ cells with ‘healthy’ cells. Thus, to fulfill this need, it is of paramount importance to understand how totipotency is established and maintained. 

Vertebrate eggs have the remarkable ability to reprogram cell fates upon somatic cell nuclear transfer (SCNT) resulting in a totipotent nuclear transfer embryo. We use this system to study the molecular processes during reprogramming to totipotency.

 

During somatic cell nuclear transfer (SCNT), the nucleus of a somatic cell (donor) gets transferred into an enucleated egg. The resulting nuclear transfer embryo is able to erase the memory of the somatic cell identity. This allows the establishment of totipotency in the laboratory.

The reprogramming efficiency of SCNT is very low since some donors are resistant to reprogramming. Previously, we could show that the cellular memory of resistant donors is stabilized by a specific epigenetic mark, the prominent histone modification H3K4 methylation. We investigate whether histone modifications, in particular H3K4 methylation, can act as epigenetic barriers for reprogramming. We aim to find approaches that allow us to manipulate or circumvent these barriers. Our work will provide fundamental insights into how reprogramming efficiencies can be improved and will promote the progress of the techniques, that allow the generation of totipotent cells in a petri dish.

During development, the totipotent zygote undergoes multiple rounds of cell division and differentiation. The arising daughter cells commit more and more to a certain cell lineage losing cellular plasticity until they reach their final cell fates, e.g. becoming a skin cell. Each differentiation step is accompanied by specific changes in gene expression to establish a stable cell state — a ‘memory’ of cell fate is acquired. This cell-fate memory is highly protected and cannot be easily changed in nature. However, in the petri dish, vertebrate eggs have the remarkable ability to reprogram cell fates when the nucleus of a somatic cell is transferred to an enucleated egg. The so-generated nuclear transfer embryo can erase the cellular memory of the previous cell identity, allowing the establishment of totipotency, and can so give rise to all cell types of the body. That has a fundamental impact on regenerative medicine.
We aim to unravel the epigenetic mechanisms that stabilize differentiated cell fates and inhibit the reprogramming of cell fates in order to achieve a fast, efficient, and complete switch in cell fate directly or within a few cell cycles.

One of the most fascinating aspects of life is that the fertilized egg (zygote) can form a full new organism. In animals, development starts with the fertilization of the oocyte by the sperm, two highly differentiated cells. The resulting cell, the zygote can form a full new organism by itself. We call this capacity ‘totipotency’ which is the highest degree of cellular plasticity. Totipotency occurs naturally for a short time window at the onset of vertebrate development. The generation of totipotent cells in the laboratory holds enormous promises for regenerative medicine since it would enable replacing ‘sick’ cells with ‘healthy’ cells. Thus, to fulfill this need, it is of paramount importance to understand how totipotency is established and maintained. 

Vertebrate eggs have the remarkable ability to reprogram cell fates upon somatic cell nuclear transfer (SCNT) resulting in a totipotent nuclear transfer embryo. We use this system to study the molecular processes during reprogramming to totipotency.

 

During somatic cell nuclear transfer (SCNT), the nucleus of a somatic cell (donor) gets transferred into an enucleated egg. The resulting nuclear transfer embryo is able to erase the memory of the somatic cell identity. This allows the establishment of totipotency in the laboratory.

The reprogramming efficiency of SCNT is very low since some donors are resistant to reprogramming. Previously, we could show that the cellular memory of resistant donors is stabilized by a specific epigenetic mark, the prominent histone modification H3K4 methylation. We investigate whether histone modifications, in particular H3K4 methylation, can act as epigenetic barriers for reprogramming. We aim to find approaches that allow us to manipulate or circumvent these barriers. Our work will provide fundamental insights into how reprogramming efficiencies can be improved and will promote the progress of the techniques, that allow the generation of totipotent cells in a petri dish.

The Hörmanseder Lab

Dr. Eva Hörmanseder

Group Leader

Marco Stock

Doctoral Researcher

Dr. Tomas Zikmund

Postdoc

Meghana Oak

Doctoral Researcher

Ana Janeva

Doctoral Researcher

Petra Hammerl

Institute Assistant

Previous Publication

  1. Oikawa M, Simeone A, Hormanseder E, Teperek M, Gaggioli V, O'Doherty A, Falk E, Sporniak M, D'Santos C, Franklin VNR, Kishore K, Bradshaw CR, Keane D, Freour T, David L, Grzybowski AT, Ruthenburg AJ, Gurdon J, Jullien J. Epigenetic homogeneity in histone methylation underlies sperm programming for embryonic transcription. Nat Commun. 2020.
  2. Hörmanseder E, Simeone A, Allen GE, Bradshaw CR, Figlmüller M, Gurdon J, Jullien J. H3K4 Methylation-Dependent Memory of Somatic Cell Identity Inhibits Reprogramming and Development of Nuclear Transfer Embryos. Cell Stem Cell. 2017.
  3. Lavagnolli T, Gupta P, Hörmanseder E, Mira-Bontenbal H, Dharmalingam G, Carroll T, Gurdon JB, Fisher AG, Merkenschlager M. Initiation and maintenance of pluripotency gene expression in the absence of cohesin. Genes Dev. 2015.
  4. Hörmanseder E, Tischer T, Mayer TU. Modulation of cell cycle control during oocyte-to-embryo transitions. EMBO J. 2013.
  5. Tischer T, Hörmanseder E, Mayer TU. The APC/C inhibitor XErp1/Emi2 is essential for Xenopus early embryonic divisions. Science. 2012.
  6. Hörmanseder E, Tischer T, Heubes S, Stemmann O, Mayer TU. Non-proteolytic ubiquitylation counteracts the APC/C-inhibitory function of XErp1. EMBO Rep. 2011.

Contact

Marie-Sophie Breuer

Administrative Assistant