title: Target genes of Topoisomerase IIβ regulate neuronal survival and are defined by their chromatin state.
abstract: 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 IIα (Top2α) to IIβ (Top2β) occurs during neuronal differentiation in vitro and in vivo. Genome-scale location analysis in stem cell-derived postmitotic neurons reveals Top2β binding to chromosomal sites that are methylated at lysine 4 of histone H3, a feature of regulatory regions. Indeed Top2β-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 Top2β protein or its activity leads to changes in transcription and chromatin accessibility at many target genes. Top2β 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 Top2β. These findings suggest a chromatin-based targeting of Top2β to regulatory regions in the genome to govern the transcriptional program associated with neuronal differentiation and longevity.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, CH-4058 Basel, Switzerland. v.tiwari@imb-mainz.de
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Tiwari
authors.forename: Lukas
authors.initials: L
authors.lastname: Burger
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Nikoletopoulou
authors.forename: Ruben
authors.initials: R
authors.lastname: Deogracias
authors.forename: Sudhir
authors.initials: S
authors.lastname: Thakurela
authors.forename: Christiane
authors.initials: C
authors.lastname: Wirbelauer
authors.forename: Johannes
authors.initials: J
authors.lastname: Kaut
authors.forename: Remi
authors.initials: R
authors.lastname: Terranova
authors.forename: Leslie
authors.initials: L
authors.lastname: Hoerner
authors.forename: Christian
authors.initials: C
authors.lastname: Mielke
authors.forename: Fritz
authors.initials: F
authors.lastname: Boege
authors.forename: Rabih
authors.initials: R
authors.lastname: Murr
authors.forename: Antoine H F M
authors.initials: AH
authors.lastname: Peters
authors.forename: Yves-Alain
authors.initials: YA
authors.lastname: Barde
authors.forename: Dirk
authors.initials: D
authors.lastname: Schübeler
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics*; D004250:DNA Topoisomerases, Type II / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D054659:Diketopiperazines; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D034622:RNA Interference; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D054659:Diketopiperazines; D010879:Piperazines; D020800:Receptor, Nerve Growth Factor; D059005:Topoisomerase II Inhibitors; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione; D004250:DNA Topoisomerases, Type II