image: STILT generates simulated protein expression of dividing cells based on measured data and a dynamic model. view more
Credit: Source: Helmholtz Zentrum München
The transcription factor Nanog plays a crucial role in the self-renewal of embryonic stem cells. Previously unclear was how its protein abundance is regulated in the cells. Researchers at the Helmholtz Zentrum München and the Technical University of Munich, working in collaboration with colleagues from ETH Zürich, now report in Cell Systems that the more Nanog there is on hand, the less reproduction there is.
Every stem cell researcher knows the protein Nanog* because it ensures that these all-rounders continue to renew. A controversial debate revolved around how the quantity of Nanog protein in the cell is regulated. "So far it was often assumed that Nanog activates itself in order to preserve the pluripotency in embryonic stem cells," explains Dr. Carsten Marr. He heads the Quantitative Single Cell Dynamics research group at the Institute of Computational Biology (ICB) of the Helmholtz Zentrum München. Together with colleagues from ETH Zürich, he and his team have developed an algorithm called STILT (Stochastic Inference on Lineage Trees) that now rebuts this assumption.
Using STILT, the scientists evaluated time-resolved protein expression data (already collected in 2015) from individual cells in which Nanog could be detected through fusion with a fluorescence protein. "We compared the Nanog dynamics that were measured in this way with three different models. One of the challenges here was the quantitative comparison of the models, and another was taking stem cell divisions into account in the algorithm," reports first author Dr. Justin Feigelman, who had moved from the Helmholtz Zentrum München to ETH Zürich as a postdoc. "The results show that Nanog is regulated by a so-called negative feedback loop, which means that the more Nanog there is in the cells, the less reproduction there will be."
Carried over from the computer to the petri dish
In order to check these results, the scientists calculated what would happen if there were an artificial increase in Nanog protein levels. "We then actually succeeded in confirming the hypothesis put forward by STILT in an additional single-cell experiment with increased Nanog," explains study leader Marr.
Thanks to their research, the scientists promise a better understanding for stem cell renewal and hope that this knowledge might be useful for medical applications in the future. "We will also be applying STILT to other time-resolved single cell data in the future, which will give us insight into the underlying molecular gene regulation mechanisms," Marr explains.
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The STILT software is freely available to other scientists on the Internet: http://www.imsb.ethz.ch/research/claassen/Software/stilt---stochastic-inference-on-lineage-trees.html
Further information
* The name is derived from Tír na nÓg, which is the "Land of Eternal Youth" according to an Irish legend. Among other jobs, Nanog is responsible for pluripotency, which is the ability that stem cells have to develop into almost any other cell type.
Background: The data were collected in the framework of an already published study from 2015 that used thousands of individual cells (Filipczyk et al., 2015, Nature Cell Biology). At that time, the ICB scientists were already able to draw unexpected conclusions regarding the regulatory network involving Nanog. http://www.helmholtz-muenchen.de/en/press-media/press-releases/2015/press-release/article/27689/index.html
Original Publication: Feigelman, J. et al. (2016): Exact Bayesian lineage tree-based inference identifies Nanog negative autoregulation in mouse embryonic stem cells. Cell Systems, doi: 10.1016/j.cels.2016.11.001 http://dx.doi.org/10.1016/j.cels.2016.11.001
The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. http://www.helmholtz-muenchen.de/en
The Institute of Computational Biology (ICB) develops and applies methods for the model-based description of biological systems, using a data-driven approach by integrating information on multiple scales ranging from single-cell time series to large-scale omics. Given the fast technological advances in molecular biology, the aim is to provide and collaboratively apply innovative tools with experimental groups in order to jointly advance the understanding and treatment of common human diseases. http://www.helmholtz-muenchen.de/icb
Technical University of Munich (TUM) is one of Europe's leading research universities, with more than 500 professors, around 10,000 academic and non-academic staff, and 40,000 students. Its focus areas are the engineering sciences, natural sciences, life sciences and medicine, com-bined with economic and social sciences. TUM acts as an entrepreneurial university that promotes talents and creates value for society. In that it profits from having strong partners in science and industry. It is represented worldwide with a campus in Singapore as well as offices in Beijing, Brussels, Cairo, Mumbai, San Francisco, and São Paulo. Nobel Prize winners and inventors such as Rudolf Diesel, Carl von Linde, and Rudolf Mößbauer have done research at TUM. In 2006 and 2012 it won recognition as a German "Excellence University." In international rankings, TUM regularly places among the best universities in Germany. http://www.tum.de/en/homepage
Freedom and individual responsibility, entrepreneurial spirit and open-mindedness: ETH Zurich stands on a bedrock of true Swiss values. Our university for science and technology dates back to the year 1855, when the founders of modern-day Switzerland created it as a centre of innovation and knowledge. At ETH Zurich, students discover an ideal environment for independent thinking, researchers a climate which inspires top performance. Situated in the heart of Europe, yet forging connections all over the world, ETH Zurich is pioneering effective solutions to the global challenges of today and tomorrow. Some 500 professors teach around 20,000 students - including 4,000 doctoral students - from over 120 countries. Their collective research embraces many disciplines: natural sciences and engineering sciences, architecture, mathematics, system-oriented natural sciences, as well as management and social sciences. The results and innovations produced by ETH researchers are channelled into some of Switzerland's most high-tech sectors: from computer science through to micro- and nanotechnology and cutting-edge medicine. Every year ETH registers around 90 patents and 200 inventions on average. Since 1996, the university has produced a total of 330 commercial spin-offs. ETH also has an excellent reputation in scientific circles: 21 Nobel laureates have studied, taught or researched here, and in international league tables ETH Zurich regularly ranks as one of the world's top universities. http://www.ethz.ch/en.html
Contact for the media: Department of Communication, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg - Tel. +49 89 3187 2238 - Fax: +49 89 3187 3324 - E-mail: presse@helmholtz-muenchen.de
Scientific Contact: Dr. Carsten Marr, Helmholtz Zentrum München - German Research Center for Environmental Health, Institute of Computational Biology, Ingolstädter Landstr. 1, 85764 Neuherberg - Tel. +49 89 3187 2158, E-mail: carsten.marr@helmholtz-muenchen.de
Journal
Cell Systems