Hierarchies in eukaryotic genome organization: Insights from polymer theory and simulations

The term "genome" refers to the complete linear DNA sequence containing all of the hereditary material possessed by an organism. One of the goals of the human genome project was to determine the sequence of the 3 billion base pairs that constitute human DNA. Despite the wealth of information this tour-de-force of scientific enterprise has generated, it is increasingly becoming clear that the cellular function of the human genome is not merely determined by the linear ordering of its DNA base pairs. In fact, many of the functional aspects of the genome are governed by its three dimensional (3D) structure, which involves meters long DNA packaged into the limiting space of a micrometer sized cell nucleus.The DNA, thus packaged, occupies a significant portion of the nucleus volume while cellular factors that read, copy, modify, and maintain the genome, occupy the remaining. Ultimately, sophisticated patterns in cellular function arise due to a coupling between the accessibility of genetic information in the packaged DNA, and the organization and activity of cellular factors within the cell nucleus. For instance, nuclear processes like transcription, translation, repair and recombination do not occur ubiquitously in the nucleus, but are spatially compartmentalized in transcription, replication and recombination factories [1-3]. Clearly, how the 3D organization of the genome modulates these nuclear processes and how the nuclear processes in turn modify genome structure are important questions in modern cell biology. A critical step in addressing these questions requires a fundamental understanding of the genome 3D structure and the physical principles governing its organization, as articulated concisely yet powerfully in the cartoon of Figure 1.Increasingly, ideas from polymer theory and simulations coupled with state-of-the-art microscopy and chromosome conformation capture techniques are being used to determine the 3D structure of the genome and the physical principles