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

Tiwari, Vijay K; Burger, Lukas; Nikoletopoulou, Vassiliki; Deogracias, Ruben; Thakurela, Sudhir; Wirbelauer, Christiane; Kaut, Johannes; Terranova, Remi; Hoerner, Leslie; Mielke, Christian; Boege, Fritz; Murr, Rabih; Peters, Antoine H F M; Barde, Yves-Alain; Schübeler, Dirk

doi:10.1073/pnas.1119798109

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Title		Target genes of Topoisomerase IIβ regulate neuronal survival and are defined by their chromatin state
Authors		Tiwari, Vijay K Burger, Lukas Nikoletopoulou, Vassiliki Deogracias, Ruben Thakurela, Sudhir Wirbelauer, Christiane Kaut, Johannes Terranova, Remi Hoerner, Leslie Mielke, Christian Boege, Fritz Murr, Rabih Peters, Antoine H F M Barde, Yves-Alain Schübeler, Dirk show all authors [1 - 15]
Published in		Proceedings of the National Academy of Sciences. 2012, vol. 109, no. 16, p. E934-43
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.
Keywords		Animals — Blotting, Western — Cell Differentiation/genetics — Cell Survival/genetics — Cells, Cultured — Chromatin/genetics — DNA Topoisomerases, Type II/genetics/metabolism — DNA-Binding Proteins/antagonists & inhibitors/genetics/metabolism — Embryonic Stem Cells/cytology/drug effects/metabolism — Female — Gene Expression Profiling — Gene Expression Regulation, Developmental — Immunoprecipitation — Male — Mice — Mice, 129 Strain — Mice, Knockout — Neurons/cytology/drug effects/metabolism — Oligonucleotide Array Sequence Analysis — Piperazines/pharmacology — Protein Binding — RNA Interference — Receptor, Nerve Growth Factor/genetics/metabolism — Reverse Transcriptase Polymerase Chain Reaction — Time Factors — Topoisomerase II Inhibitors/pharmacology
Identifiers		DOI: 10.1073/pnas.1119798109 PMID: 22474351
Full text		Article (Published version) (3.8 MB) - Free access
Structures		Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement
Research group		Epigénétique et développement (950)
Citation (ISO format)		TIWARI, Vijay K et al. Target genes of Topoisomerase IIβ regulate neuronal survival and are defined by their chromatin state. In: Proceedings of the National Academy of Sciences, 2012, vol. 109, n° 16, p. E934-43. doi: 10.1073/pnas.1119798109 https://archive-ouverte.unige.ch/unige:43451