Three pieces in genome organization

Genomes are arranged in a highly organized manner that varies based on cell type and life phase. This three-dimensional organization plays a critical role in transcriptional regulation, and its disruption is often associated with disease.

In this talk, I will explore three facets of genome organization: the architecture of human chromosomes, the molecular determinants of gene structural ensembles, and the consequences of gene positioning in mammalian genomes. First, I will explain how the structure of interphase chromosomes can be traced to two key physical mechanisms: phase separation and motor activity. Chromosome architecture is encoded by the sequence of epigenetic marks, similar to how protein structure is dictated by its amino acid sequence. However, unlike proteins, these epigenetic marks are dynamically rewritten during cell differentiation, affecting both the 3D organization of chromosomes and gene expression in various cell types. Along with phase separation of epigenetic marks, motor activity compacts chromosomes lengthwise, leading to the formation of chromosomal territories and preventing knotting. I will illustrate how the interplay between these two mechanisms—lengthwise compaction and phase separation—shapes the topology of chromosomes across evolution. These insights have driven the development of a physical theory for genome folding, which allows for precise and accurate predictions of chromosomal 3D conformations. Next, I will discuss how the mechanical properties of DNA, together with nucleosome density and positioning and the effect of supercoiling, influence the structural ensembles of genes. Finally, I will discuss how a novel comparative approach to mammalian genomics demonstrates how the positioning of genes along the genome imposes evolutionary constraints.

Together, these three perspectives underscore the profound relationship between genome structure and gene regulation, each operating at distinct length scales.