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Cellular function requires a multitude of proteins and co-factors that allow chromosomal DNA to be properly transcribed, duplicated, repaired, and segregated. In turn, these processes depend on the three-dimensional (3D) folding of chromosomes, and are influenced by changes in the helical structure of DNA, so-called supercoiling. We and others have suggested that supercoiling is functionally connected to chromosome 3D organization, but direct evidence has been lacking. Collectively, our investigations now show that a family of chromosome-folding machines, called Structural Maintenance of Chromosome protein complexes, indeed link supercoiling to chromosome 3D organization (e.g., Nature 2011, Cell Rep. 2015, Science Adv. 2022, Nature 2023). The purpose of the presented project is to determine how this mostly unknown interplay contributes to chromosome function. The specific aims are to:1)  Establish the molecular mechanisms of the DNA supercoiling-chromosome folding interplay.2) Determine how the supercoiling-folding interplay influence transcription and early development.This will be achieved by combining a variety of methods such as high-resolution micro-C analysis, single molecule analysis, high resolution microscopy, various in vivo models, and a unique marker for DNA supercoiling that we recently discovered. This will unravel new fundamental principles of chromosome organization and provide insights into the cellular defence against disease-related chromosomal aberrations.