RT Journal Article SR Electronic T1 Genome urbanization: Clusters of topologically co-regulated genes delineate functional compartments in the genome of S. cerevisiae JF bioRxiv FD Cold Spring Harbor Laboratory SP 064667 DO 10.1101/064667 A1 Maria Tsochatzidou A1 Maria Malliarou A1 Joaquim Roca A1 Christoforos Nikolaou YR 2016 UL http://biorxiv.org/content/early/2016/08/12/064667.abstract AB The eukaryotic genome evolves under the dual constraint of maintaining co-ordinated gene transcription and performing effective DNA replication and cell division, the coupling of which brings about inevitable DNA topology tension. This is resolved and in some cases even harnessed by the genome through the function of DNA topoisomerases, as has been shown in the concurrent transcriptional activation and suppression of genes upon transient deactivation of topoisomerase II (topoll). The scope of this work is to identify extended genomic domains with similar response to topological stress and to study their structural and functional properties. By analyzing a genome wide run-on experiment upon thermal inactivation of topoII in S. cerevisiae we were able to define 116 gene clusters of concerted response (either positive or negative) to topological stress. A comprehensive analysis of these topologically co-regulated gene clusters revealed pronounced preferences regarding their functional, regulatory and structural attributes. Our findings point towards a particular genome compartmentalization, according to which genes that negatively respond to topological stress, are positioned in gene-dense pericentromeric regions, are more conserved and associated to essential functions, while up-regulated gene clusters are preferentially located in the gene-sparse nuclear periphery, associated with secondary functions and under complex regulatory control. This multi-faceted “division of labour” is much resembling a “genome urbanization” process. We propose that genome architecture evolves with a core of essential genes occupying a compact genomic “old town”, whereas more recently acquired, condition-specific genes tend to be located in a more spacious “suburban” genomic periphery.Significance In all eukaryotes, the relative positions of genes are constrained by the need for complex transcriptional regulation and effective DNA replication, both of which lead to the accumulation of DNA supercoiling. Here, we perform a concise analysis of the genome architecture of S. cerevisiae, by examining the way genes respond to the inactivation of topoisomeraseII. We uncover a fundamental functional compartmentalization, according to which, conserved, essential genes are more prone to topological stress and localize in gene-dense chromatin in the center of the nucleus, contrary to stress-responsive genes, occupying the nuclear periphery, where broader intergenic regions may propel transcription by harnessing topological tension. Our findings suggest a vital role of DNA topological constraints in the evolution of eukaryote genome architecture.