The dynamic three-dimensional organization of the diploid yeast genome

Abstract

The budding yeast Saccharomyces cerevisiae is a long-standing model for the three-dimensional organization of eukaryotic genomes. However, even in this well-studied model, it is unclear how homolog pairing in diploids or environmental conditions influence overall genome organization. Here, we performed high-throughput chromosome conformation capture on diverged Saccharomyces hybrid diploids to obtain the first global view of chromosome conformation in diploid yeasts. After controlling for the Rabl-like orientation using a polymer model, we observe significant homolog proximity that increases in saturated culture conditions. Surprisingly, we observe a localized increase in homologous interactions between the HAS1-TDA1 alleles specifically under galactose induction and saturated growth. This pairing is accompanied by relocalization to the nuclear periphery and requires Nup2, suggesting a role for nuclear pore complexes. Together, these results reveal that the diploid yeast genome has a dynamic and complex 3D organization.Most of the DNA in human, yeast and other eukaryotic cells is packaged into long thread-like structures called chromosomes within a compartment of the cell called the nucleus. The chromosomes are folded to fit inside the nucleus and this organization influences how the DNA is read, copied, and repaired. The folding of chromosomes must be robust in order to protect the organism’s genetic material and yet be flexible enough to allow different parts of the DNA to be accessed in response to different signals.A biochemical technique called Hi-C can be used to detect the points of contact between different regions of a chromosome and between different chromosomes, thereby providing information on how the chromosomes are folded and arranged inside the nucleus. However, most animal cells contain two copies of each chromosome, and the Hi-C method is not able to distinguish between identical copies of chromosomes. As such, it remains unclear how much the chromosomes that can form pairs actually stick together in a cell’s nucleus.Unlike humans and most organisms, two distantly related budding yeast species can mate to produce a “hybrid” in which the chromosome copies can easily be distinguished from each other. Kim et al. now use Hi-C to analyze how chromosomes are organized in hybrid budding yeast cells.The experiments reveal that the copies of a chromosome contact each other more frequently than would be expected by chance. This is especially true for certain chromosomal regions and in hybrid yeast cells that are running out of their preferred nutrient, glucose. In these cells, the regions of both copies of chromosome 13 near a gene called TDA1 are pulled to the edge of the nucleus, which helps the copies to pair up and the gene to become active. The protein encoded by TDA1 then helps turn on other genes that allow the yeast to use nutrients other than glucose.Many questions remain about how and why DNA is organized the way it is, both in yeast and in other organisms. These findings will help guide future experiments testing how the two copies of each chromosome pair, as well as what purpose, if any, this pairing might serve for the cell. A better understanding of the fundamental process of DNA organization and its implications may ultimately lead to improved treatments for genetic diseases including developmental disorders and cancers.