Landscapes of Genomic Architecture Across Evolution

The human genome is composed of 46 DNA molecules — the chromosomes — with a combined length of about two meters. Chromosomes are stored in the cell nucleus in a very organized fashion that is specific to the cell type and phase of life; 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 blueprint of such architecture stored?

In this talk, I will demonstrate how 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 that decorate 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.

This idea led to the development of a physical theory for the folding of genomes, which enables predicting the spatial conformation of chromosomes with unprecedented accuracy and specificity. Finally, I will demonstrate how the different energy terms present in our model impact the topology of chromosomes across evolution. Our results open the way for studying functional aspects of genome architecture along the three of life.