INTEGER: Integrative Analyse eines Essentiellen Epigenetischen Regulators

DNA甲基化是哺乳动物重要的表观遗传标记。它是胚胎发育和细胞分化所必需的，它的改变是许多遗传性或散发性人类疾病的根源，从神经退化到免疫缺陷，以及许多癌症。为了更好地预防、诊断和治疗这些不同的疾病，有必要深入了解控制哺乳动物DNA甲基化的分子机制。我们的项目就是在这个角度下存在的。我们的起点是一种蛋白质，它是DNA甲基化必不可少的，但其工作模式仍未被完全了解：uhrf1。在德国、法国、英国和日本团队的合作下，我们最近在这个关键的分子演员的功能方面取得了意想不到的重要结果。在拟议的项目中，我们将使用这些最近的结果来测试关于该蛋白质在DNA甲基化中作用的不同假说。为实现这一目标，我们组建了一个由互补领域的专家小组组成的国际联盟。法国的一个团队将带来其在分子生物学和基因组学方面的专业知识。德国的两个团队将贡献他们在染色质生物化学、结构生物学、基因组编辑和干细胞生物学方面的专业知识。我们将一起在定制的小鼠ES细胞系统中进行生化调查和实验，以阐明uhrf1的功能，并更广泛地了解DNA甲基化的机制。这些成果将通过口头陈述、科学论文和出版物进行交流，并将为国家和国际科学界作出贡献。作为该项目的重要组成部分，我们将参与大学教学，我们还将招聘初级研究人员并为他们提供优质的科学培训，所有这些都将为法国和德国社会经济体系的吸引力和竞争力做出积极贡献。最后，我们将通过专门的活动与公众互动，向非专业人士展示我们的生物学研究。

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.