In human cells, two meters of DNA sequence are compressed into a nucleus whose linear size is five orders of magnitude smaller. Deciphering how this amazing structural organization is achieved and how DNA functions can ensue in the environment of a cell’s nucleus represent central questions for contemporary biology.

Here, I embrace this challenge by establishing a comprehensive framework of microscopy and sequencing technologies coupled with advanced analytical approaches, aimed at addressing three fundamental highly-interconnected questions: 1) What are the design principles that govern DNA compaction? 2) How does genome structure vary between different cell types as well as among cells of the same type? 3) What is the link between genome structure and function? To this aim, we have devised a powerful method for Genomic loci Positioning by Sequencing (GPSeq), which allows genome-wide measurements of the distance of genomic loci to the nuclear periphery. Using GPSeq, we are generating reproducible maps of radial genome organization in human cells, in order to reveal radial gradients of genetic and epigenetic features as well as gene expression in various cell and tissue types. In parallel, we are developing high-end microscopy tools for simultaneous localization of dozens of genomic locations at high resolution in thousands of single cells.