Genome topology and mechanical stress

Introduction

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 absorb mechanical forces. Inter-chromosomal contacts and nuclear envelope-associated domains contribute to transducing mechanical stress when cells experience compression, stretching, or interstitial migration.

Objectives

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).

Work Package 1 (WP1)

In WP1, we will investigate:

1. How the topological context influences nucleosome chirality and the epigenetic landscape.
2. How the inter-chromosomal connections mediated by topoisomerase activities influence genome mechanics.
3. How chromosome topology contributes to generating aberrant DNA structures and how DNA damage induces topological changes.
4. How the nuclear envelope and the nucleolus influence chromatin topology and histone modifications.
5. How nuclear deformation affects genome integrity and the topological landscape.

Work Package 2 (WP2)

In WP2, we will study:

1. The ATR and ATM-mediated mechanisms controlling nuclear and genome integrity and mechanics, under unperturbed conditions or in response to mechanical stress.
2. How the topological context of the genome responds to mechanical forces generated by cell compression or stretching and the implications for fragile site expression.
3. How mechanical stress generated by interstitial migration influences genome topology, chromosome instability, and the mechanisms causing amplification of specific chromosomal loci.

Expected Results

The expected results may contribute to elucidating the mechanisms controlling nuclear and genome mechanics and those pathological processes promoting certain mechano-diseases.