Multiscale modeling of chromatin: from fibers to genes to chromosomes

Digitizing the human genome and the genomes of many model organism has been a landmark achievement of modern science. However, deciphering thetertiary organization of DNA's folding in the cell, and hence accessibility to the cellular machinery, is essential for understanding how genetic information is replicated, transcribed, silenced, and edited in fundamental processes including gene expression, DNA replication and repair, cell division and differentiation, and cancer progression. To address this multiscale folding challenge, many computational approaches have been developed to complement experimental structure determination techniques. I will describe our coarse-grained mesoscale chromatin model and novel equilibrium and dynamics algorithms to sample higher-order chromatin structure as a function of internal and external parameters and fold genes from first principles, interpret folding mechanisms relevant to cell differentiation and cancer progression, and simulate chromatin conformations consistent from experimental chromosome conformation capture contact maps. The studies reveal intriguing hierarchical looping mechanisms in genes that may play a role in gene silencing, protein-driven transitions of chromatin condensation that play a role in human lymphoma, and how a combination of epigenetic factors regulates chromatin topologies on both local and global scales.