INTEGER: Integrative Analyse eines Essentiellen Epigenetischen Regulators

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DNA methylation is an essential epigenetic mark in mammals. It is necessary for embryonic development, for cell differentiation, and its alteration is at the root of many hereditary or sporadic human diseases, ranging from neuro-degeneration, to immunodeficiency, and many cancers. To better prevent, diagnose, and treat these different diseases, it is necessary to come to a fine understanding of the molecular mechanisms that govern the methylation of mammalian DNA. Our project exists within this perspective. Our starting point is a protein that is absolutely required for the methylation of DNA, but whose mode of operation is still imperfectly understood: UHRF1. In a collaboration between German, French, English and Japanese teams, we have recently achieved unexpected and important results regarding the function of this crucial molecular actor. In the proposed project, we will use these recent results to test different hypotheses about the role of this protein in DNA methylation. To achieve this, we have assembled an international consortium of expert teams in complementary fields. One team in France will bring its expertise in molecular biology and genomics. Two teams in Germany will contribute their expertise in chromatin biochemistry, structural biology, genome editing, and stem cell biology. Together, we will perform biochemical investigations and experiments in custom mouse ES cell systems to clarify the function of UHRF1 and, more broadly, to better understand the mechanism of DNA methylation. These results will be communicated through oral presentations, scientific papers and publications, and will contribute to the national and international scientific community. As an important part of the project, we will participate in university teaching, and we will also recruit junior researchers and provide them with quality scientific training, all of which will contribute positively to the attractiveness and competitiveness of the French and German social and economic systems. Finally, we will interact with the general public through dedicated events presenting our biological research to non-specialists.