The Three-Dimensional Architecture of the Human Genome: It's Nuclear Physics!

Abstract

The human genome is composed of 46 DNA molecules — the chromosomes — with a combined length of about 2 meters. Chromosomes are stored in the cell nucleus in a very organized fashion that is specific to the cell type; this three-dimensional architecture is a key element of transcriptional regulation and its disruption often leads to disease. What is the physical mechanism leading to genome architecture? If the DNA contained in every human cell is identical, where is the information — the blueprint — of such architecture stored? In a series of works, we were able to demonstrate that the architecture of interphase chromosomes is encoded in the one-dimensional sequence of epigenetic markings much as three-dimensional protein structures are determined by their one-dimensional sequence of amino acids. In contrast to the situation for proteins, however, the sequence code provided by the epigenetic marks decorating the chromatin fiber is not fixed but is dynamically rewritten during cell differentiation, modulating both the three-dimensional structure and gene expression in different cell types. In vivo, segments of chromatin characterized by homogeneous epigenetic markings undergo a process similar to phase separation under the action of the proteome present in the nucleus. This process forms liquid droplets, which rearrange dynamically by splitting and fusing, thereby modulating DNA distal interactions and generating the genomic compartments characteristic of chromosomal architecture. Our theory — together with our computational tools — allows predicting and studying the spatial conformation of genomes with unprecedented accuracy and specificity, thus opening the way to the study of the functional aspects of genome architecture.