We showed that DNA topoisomerase Ⅱbeta (topo Ⅱbeta) is essential for transcriptional activation of certain genes in terminally differentiating neurons (J Biol Chem, 2001;PLoS One, 2008).Genomic locations of a subset of genes that is regulated by topo Ⅱbeta tend to locate right next to long AT-rich intergenic regions (thus termed LA genes).We mapped the in vivo action sites of topo Ⅱbeta (toposites) by a novel functional ChIP technology (eTIP), in that DNA fragments were separated into two fractions, G-segment (covalently-linked to the enzyme) and T-segment (noncovalently bound to the enzyme).T-segments that are to be transferred through the gap generated in the G-segments appeared to be originated from distant genomic loci.Through a genomewide search for toposites using tiling arrays, distal strand passage events were detected in and around LA genes.It is very likely that the distal passage by the enzyme is involved in the activation of these genes.The targeted action of topo Ⅱbeta in vivo may be assisted by other factor(s).We found recently that topo Ⅱbeta forms a complex with a multifunctional nuclear protein (hnRNP U/SAF-A/SP120) in the presence ofRNA (J Biol Chem, 2010).SP120 selectively binds to AT-rich DNAs associated with the nuclear matrix (MAR).A high-throughput sequencing approach for collinear mapping of toposites (eTIPseq) and SP 120-binding sites (ChIP-seq) revealed the presence of toposites overlapping with SP 120 sites.The type Ⅱ topoisomerase, a modulator of DNA topology, appears to mediate the interaction between distant genomic loci to alter the global chromatin topography.