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 topological 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 (topoII). 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 consistent 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.