Damage in the DNA inhibits transcription of genes by RNA polymerase II, which copies the genetic information of DNA into RNA. This impediment of RNA polymerase II results in severe cellular dysfunction and accelerated aging. Through a consortium combining unique complementary knowledge and expertise, we can study for the first time the causes and consequences of DNA damage from the perspective of a single molecule to that of a whole organism. Using this approach, we will study what exactly happens to RNA polymerase when encountering DNA damage, and directly link this to the consequences at the cellular and organism level.

In our bodies genes need to be activated at the right time and the right place. Many of these genes are activated by pieces of DNA that are located far away in the genome. The folding of our genome plays an important role in the correct regulation of these genes. We will investigate which factors are important in this process. This will lead to a better understanding how genes are regulated during embryonal development and what happens in developmental disorders.

Sequencing of the human genome, amongst many others, initiated a new age in human biology, offering unprecedented opportunities to improve human health and to stimulate scientific, industrial and economic activity. Following this historical milestone in science, the emphasis rapidly moved to biological interpretation of the genome sequencing information. This biological interpretation relies heavily on the field of proteomics. Proteomics is the analysis of protein function on a large scale, including the measurement of protein expression profiles, protein post-translational modifications and protein networks to determine how they are involved in and regulate development, health and disease and many other biological processes. In the past decade, several countries have recognized the importance of proteomics in understanding the biology of humans, animals, plants, pathogens and model organisms, and as such made great financial efforts to fund proteomics-related research and proteomics infrastructures. The EU has also granted significant amounts of funding to proteomics-related programs. Through these investments, the field of proteomics has matured immensely, and today offers incredibly powerful tools to study the biology of cells, tissues and whole organisms and to reveal, at the most fundamental level, causes of disease processes. The Netherlands has been able to achieve, through the NGI-supported Netherlands Proteomics Centre (NPC), a leading role in the development of these enabling proteomics technologies, promoting them to be adopted by selected groups within the Dutch life science community. Following the successful pioneering stage of the NPC, leading life science institutes in the Netherlands have now realised that, in the next decade, access to high-quality proteomics facilities and expertise will be indispensable in enabling further major scientific breakthroughs. Therefore, the pivotal next step will be to harvest investments made by the NPC and to bring proteomics to the next stage. Proteins@Work will catalyze a much larger proteomics related research program with access to large-scale state-of-the-art proteomics facilities, thus allowing the community to chart simultaneously and quantitatively all proteins in human cells and tissues, in order to answer complex biological questions. As proteins are at the core of all life processes, offering access to a large-scale proteomics infrastructure will have wide implications in health, food/nutrition and biotechnology. Collectively, the idea has emerged that proteomics should not only be organized at a national level, but also with a primary focus on open access to state-of-the-art proteomics technologies and expertise for the entire life sciences community in the Netherlands. The Netherlands is very well positioned to implement the national proteomics facility, termed Proteins@Work, proposed here. Over the last decade, research groups from all over the country and in all branches of the life sciences have become involved in proteomics-associated research programs within the framework of the NPC. Such programs are now well embedded in the participating research infrastructures, who contributed about 50% of the 60 million euro invested in proteomics in the Netherlands in the period 2009-2013. The result of this nationwide effort is that Dutch proteomics research is ranked 5th in the world (2nd in Europe) based on scientific output. Through this proposal, we ask for inclusion in the national roadmap of the proposed Proteins@Work Large Scale Proteomics Research Facility, and for financial support for a globally renowned proteomics-associated research program in the Netherlands. This involves investment in a national proteomics core facility, constantly updated with state-of-the-art equipment and tools, supported by well-trained facility managers, bioinformaticians, programmers and technicians, and providing open and transparent, albeit competitive, access for top researchers in the life sciences nationally. The proposed Proteins@Work facility and its associated research program will address all areas of the life sciences, ranging from health and regenerative and personalised medicine, to food and nutrition, but also processes in biotechnology e.g. industrial fermentation processes and the development of biopharmaceuticals. The facility therefore fits excellently within the priorities of the Dutch government (?topsectorenplan?) and the EU, and will contribute significantly towards answering current and upcoming societal challenges, as well as improving the scientific position and industrial innovation climate in the Netherlands.

The early mammalian epiblast consists of pluripotent cells that differentiate into three germ layers—ectoderm, mesoderm, and endoderm—during gastrulation. The mammalian epiblast is heterogeneous, with stochastic transcriptomic and epigenomic differences influencing their response to signals. Understanding how such stochastic cells make robust fate decisions is a major challenge requiring accessible models, live-cell imaging, single-cell multi-omics, and computational modeling. By combining “gastruloids,”, a mouse embryo-like structure generated from stem cells, with these technologies, our multidisciplinary team will define cellular states and trajectories to advance knowledge of lineage specification and regenerative medicine.