Chromosomes are often represented as X-shaped structures. However, they adopt this shape only when a cell is dividing. During the rest of the life of a cell –called the interphase– chromosomes are decondensed and occupy the whole volume of the cell nucleus. Our understanding of how chromosomes are organized and folded in 3D space in the nucleus during interphase has improved tremendously over the past decades. It appears clearly that this 3D organization relates closely to the many biological processes operating on chromosomes. However, the physical principles underlying this organization remain partially understood due to the lack of tools to directly exert and measure forces on chromosomes in vivo and probe their material properties. To address this gap, we have developed a novel approach to mechanically manipulate chromosomes in the nucleus of a living cell using magnetic forces. It consists in targeting iron-containing nanoparticles to a small portion of a chromosome and applying a controlled magnetic field. With this approach, we made the first measurements of how an interphase chromosome, in a living cell, responds to a point force. We characterized the viscoelastic properties of chromosomes and found that the material that makes up chromosomes is surprisingly fluid. Its response to force is consistent with a model of a free polymer in liquid, challenging the currently-held view of the interphase nucleus as a highly crowded and topologically entangled environment. Our new approach also opens avenues for future research to probe how the physical properties of the genome relate to genome functions, including transcription, chromosome segregation, DNA damage repair and replication.

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