Thermodynamic Pathways to Genome Spatial Organization in the Cell Nucleus

The architecture of the eukaryotic genome is characterized by a high degree of spatial organization. Chromosomes occupy preferred territories correlated to their state of activity and, yet, displace their genes to interact with remote sites in complex patterns requiring the orchestration of a huge number of DNA loci and molecular regulators. Far from random, this organization serves crucial functional purposes, but its governing principles remain elusive. By computer simulations of a statistical mechanics model, we show how architectural patterns spontaneously arise from the physical interaction between soluble binding molecules and chromosomes via collective thermodynamics mechanisms. Chromosomes colocalize, loops and territories form, and find their relative positions as stable thermodynamic states. These are selected by thermodynamic switches, which are regulated by concentrations/affinity of soluble mediators and by number/location of their attachment sites along chromosomes. Our thermodynamic switch model of nuclear architecture, thus, explains on quantitative grounds how well-known cell strategies of upregulation of DNA binding proteins or modification of chromatin structure can dynamically shape the organization of the nucleus.     

酵母双杂交筛选与果蝇C(2)M相互作用的蛋白

同源染色体联会时形成的联会复合体(Synaptonemal complex, SC)是由减数分裂前期Ⅰ多种蛋白质聚集而成的超级复合结构。生殖细胞特异性的核蛋白C(2)M(Crossover suppressor on 2 of Manheim)在染色体上高度聚集可以诱导SC的形成。本文采用酵母双杂交方法,利用C(2)M的诱饵表达载体筛选果蝇cDNA文库,共发现40个可能与C(2)M相互作用的蛋白,包括多种DNA及组蛋白结合蛋白、ATPase、转录调节因子。从筛选的结果中,选取wech和Psf1基因构建了转基因果蝇,并在生殖细胞中进行了基因沉默,结果显示联会复合体的消失受到延迟。上述结果表明Wech和Psf1蛋白可能与C(2)M形成复合物,共同参与联会复合体的形成或其稳定性的维持。     

Structure and dynamics of interphase chromosomes

During interphase chromosomes decondense, but fluorescent in situ hybridization experiments reveal the existence of distinct territories occupied by individual chromosomes inside the nuclei of most eukaryotic cells. We use computer simulations to show that the existence and stability of territories is a kinetic effect that can be explained without invoking an underlying nuclear scaffold or protein-mediated interactions between DNA sequences. In particular, we show that the experimentally observed territory shapes and spatial distances between marked chromosome sites for human, Drosophila, and budding yeast chromosomes can be reproduced by a parameter-free minimal model of decondensing chromosomes. Our results suggest that the observed interphase structure and dynamics are due to generic polymer effects: confined Brownian motion conserving the local topological state of long chain molecules and segregation of mutually unentangled chains due to topological constraints.     

Genomic organization of evolutionarily correlated genes in bacteria: limits and strategies

The need for efficient molecular interplay in time and space within a cell imposes strong constraints that could be partially relaxed if relative gene positions along chromosomes were appropriate. Comparative genomics studies have demonstrated the short-scale conservation of gene proximity along bacterial chromosomes. Additionally, the long-range periodic positioning of evolutionarily correlated genes within Escherichia coli has recently been highlighted. To gain further insight into these different genetic organizations, we examined the compromise between chromosomal proximity and periodicity for all available eubacterial genomes by evaluating groups of evolutionarily correlated genes from a benchmark data set. In enterobacteria, strict chromosomal proximity is found to be limited to groups under 20 genes, whereas periodicity is significant in all groups over 50. The E. coli K12 genome bears 511 periodic genes (12% of the genome), whose orthologs are found to be periodic in all eubacterial phyla. These periodic genes predominantly function in macromolecular synthesis and spatial organization of cellular components. They are enriched in essential and housekeeping genes and tend to often be constitutively expressed. On this basis, it is argued that chromosomal proximity and periodicity are ubiquitous complementary genomic strategies that favor the build-up of local concentrations of co-functional molecules. In particular, the periodic layout may facilitate chromosome folding to spatially organize the construction of major cell components. The transition at 20 genes is reminiscent of the size of the longest operons and of topological microdomains. The range for which DNA neighborhood optimizes biochemical interactions might therefore be defined by DNA topology.