TOPOMECH · Genome topology and mechanical stress

The nucleus is the stiffest organelle in the cell and is constantly challenged by intrinsic and extrinsic forces that deform the nuclear envelope. Chromosomes are mechanical objects that can sense, transduce and adsorb mechanical forces. Inter-chromosomal contacts and nuclear envelope-associated domains contribute to transduce mechanical stress when cells experience compression, stretching or interstitial migration. We aim to study the mechanical properties of the chromosomes and how genome integrity and the chromatin topological landscape are affected by nuclear deformations. We will combine mechanistic, genetic and genomic studies in yeast (WP1) with genomic, imaging and microfluidic approaches in mammalian cells (WP2). In WP1 we will investigate i) how the topological context influences nucleosome chirality and the epigenetic landscape; ii) how the inter-chromosomal connections mediated by topoisomerase activities influence genome mechanics; iii) how chromosome topology contributes to generate aberrant DNA structures and how DNA damage induces topological changes; iv) how the nuclear envelope and the nucleolus influence chromatin topology and histone modifications; v) how nuclear deformation affects genome integrity and the topological landscape. In WP2 we will study: i) the ATR and ATM-mediated mechanisms controlling nuclear and genome integrity and mechanics, under unperturbed conditions or in response to mechanical stress; ii) how the topological context of the genome responds to mechanical forces generated by cell compression or stretching and the implications for fragile site expression; iii) how mechanical stress generated by interstitial migration influences genome topology, chromosome instability, and those mechanisms causing amplification of specific chromosomal loci. The expected results may contribute to elucidate the mechanisms controlling nuclear and genome mechanics and those pathological processes promoting certain mechano-diseases.