Proceedings of the National Academy of Sciences - PNAS, 2012-04, Vol.109 (16), p.E934-E943
2012
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- Autor(en) / Beteiligte
- Titel
- Target genes of Topoisomerase IIβ regulate neuronal survival and are defined by their chromatin state
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2012-04, Vol.109 (16), p.E934-E943
- Ort / Verlag
- United States: National Acad Sciences
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.1119798109Titel-ID: cdi_crossref_primary_10_1073_pnas_1119798109
- Format
- –
- Schlagworte
- Animals, Biological Sciences, Blotting, Western, Cell cycle, Cell Differentiation - genetics, Cell survival, Cell Survival - genetics, Cells, Cultured, Chromatin, Chromatin - genetics, Degeneration, Differentiation, DNA biosynthesis, DNA topoisomerase (ATP-hydrolysing), DNA Topoisomerases, Type II - genetics, DNA Topoisomerases, Type II - metabolism, DNA-Binding Proteins - antagonists & inhibitors, DNA-Binding Proteins - genetics, DNA-Binding Proteins - metabolism, Embryonic Stem Cells - cytology, Embryonic Stem Cells - drug effects, Embryonic Stem Cells - metabolism, Female, Gene Expression Profiling, Gene Expression Regulation, Developmental, Genomes, genomics, Histone H3, Immunoprecipitation, Longevity, Lysine, Male, Mice, Mice, 129 Strain, Mice, Knockout, Neural stem cells, Neurons, Neurons - cytology, Neurons - drug effects, Neurons - metabolism, Oligonucleotide Array Sequence Analysis, Piperazines - pharmacology, PNAS Plus, Promoters, Protein Binding, Receptor, Nerve Growth Factor - genetics, Receptor, Nerve Growth Factor - metabolism, Regulatory sequences, Replication, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Stem cells, Time Factors, Topoisomerase II Inhibitors - pharmacology, Transcription