How to build a yeast nucleus

Abstract

Biological functions including gene expression and DNA repair are affected by the 3D architecture of the genome, but the underlying mechanisms are still unknown. Notably, it remains unclear to what extent nuclear architecture is driven by generic physical properties of polymers or by specific factors such as proteins binding particular DNA sequences. The budding yeast nucleus has been intensely studied by imaging and biochemical techniques, resulting in a large quantitative data set on locus positions and DNA contact frequencies. We recently described a quantitative model of the interphase yeast nucleus in which chromosomes are represented as passively moving polymer chains. This model ignores the DNA sequence information except for specific constraints at the centromeres, telomeres, and the ribosomal DNA (rDNA). Despite its simplicity, the model accounts for a large majority of experimental data, including absolute and relative locus positions and contact frequency patterns at chromosomal and subchromosomal scales. Here, we also illustrate the model's ability to reproduce observed features of chromatin movements. Our results strongly suggest that the dynamic large-scale architecture of the yeast nucleus is dominated by statistical properties of randomly moving polymers with a few sequence-specific constraints, rather than by a large number of DNA-specific factors or epigenetic modifications. In addition, we show that our model accounts for recently measured variations in homologous recombination efficiency, illustrating its potential for quantitatively understanding functional consequences of nuclear architecture.

Quantified effects of chromosome-nuclear envelope attachments on 3D organization of chromosomes

“…First, the abundance of intra-arm interactions in Drosophila may also be dictated by robust homolog pairing that competes away non-homologous contacts 61 . Second, chromosome organization in the yeast nucleus can be explained by the confinement of chromosomes and tethering of chromosome centromere and telomere to the NE 14,15 . Finally, non-specific (entropic) forces can drive the self-organization of polymers 38,51,57,62 .…”

“…Heterogeneous interaction models allow affinity for the NE to vary along the chromosome fiber; several Downloaded by [UQ Library] at 01: 10 15 June 2015 models have specifically investigated the effects of chromosome tethers positioned at the centromeres and telomeres 11,12,14,15,[17][18][19] . These studies in yeast have led to several predictions: the 3D position of a gene can be altered due to the presence of an NE tether positioned within 10 kb 11 ; removal of chromosomal tethers at the centromere increases chromosome mobility as quantified by its confinement radius 18 ; the presence of Chr-NE tethers affects the distribution of telomere-telomere distances 17 ; the position of chromosomes within the nucleus may be altered due to a combination of Chr-NE tethering and volume exclusion 12 ; and the distribution of distances between the spindle pole body and the silent mating locus depends on tethering at the telomere 11 .…”

“…In yeast, computational studies have considered a range of models differing in the number of attachments they consider 11,12,14,15,17,18 . Homogeneous interaction models assume all chromosome sites interact equally with the NE due to the complete presence or absence of attachments at all sites along the chromosome fiber 17 .…”

“…In recognition of this growing body of evidence, many computational studies of genome organization now incorporate the specific sites of Chr-NE attachment as model parameters [11][12][13][14][15][16][17] .…”

Chromosome position determines the success of double-strand break repair

“…These observations have been extended by the use of chromosome conformation capture approaches (3,4) to map the relative positions of loci along each chromosome based on their frequencies of crosslinking (contact frequencies) with many other sites in the genome. Previous studies have shown that telomere-associated sequences preferentially recombine with other telomere-associated loci whereas centromere-linked sites selectively recombine with other centromere-linked loci (5)(6)(7). However, such preferences, presumably caused by the constraints of tethering, may not reflect the general behavior of most sequences undergoing homologous recombination.…”