Target genes of Topoisomerase II? regulate neuronal survival and are defined by their chromatin state

Topoisomerases are essential for DNA replication in dividing cells, but their genomic targets and function in postmitotic cells remain poorly understood. Here we show that a switch in the expression from Topoisomerases II? (Top2?) to II? (Top2?) occurs during neuronal differentiation in vitro and in vivo. Genome-scale location analysis in stem cell-derived postmitotic neurons reveals Top2? binding to chromosomal sites that are methylated at lysine 4 of histone H3, a feature of regulatory regions. Indeed Top2?-bound sites are preferentially promoters and become targets during the transition from neuronal progenitors to neurons, at a time when cells exit the cell cycle. Absence of Top2? protein or its activity leads to changes in transcription and chromatin accessibility at many target genes. Top2? deficiency does not impair stem cell properties and early steps of neuronal differentiation but causes premature death of postmitotic neurons. This neuronal degeneration is caused by up-regulation of Ngfr p75, a gene bound and repressed by Top2?. These findings suggest a chromatin-based targeting of Top2? to regulatory regions in the genome to govern the transcriptional program associated with neuronal differentiation and longevity.