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

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

Research output: Chapter in Book/Report/Conference proceedingChapter

71 Citations (Scopus)

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.
Original languageEnglish
Title of host publicationProceedings of the National Academy of Sciences
PagesE934-43
DOIs
Publication statusPublished - 2012

Publication series

NameProceedings of the National Academy of Sciences
Volume109

Fingerprint

Type II DNA Topoisomerase
Chromatin
Nucleic Acid Regulatory Sequences
Neurons
Stem Cells
Genome
Genes
Premature Mortality
DNA Replication
Histones
Lysine
Cause of Death
Cell Cycle
Up-Regulation
Proteins

Cite this

Tiwari, V. K., Burger, L., Nikoletopoulou, V., Deogracias, R., Thakurela, S., Wirbelauer, C., ... Schübeler, D. (2012). Target genes of Topoisomerase IIβ regulate neuronal survival and are defined by their chromatin state. In Proceedings of the National Academy of Sciences (pp. E934-43). (Proceedings of the National Academy of Sciences; Vol. 109). https://doi.org/10.1073/pnas.1119798109
Tiwari, Vijay K ; Burger, Lukas ; Nikoletopoulou, Vassiliki ; Deogracias, Ruben ; Thakurela, Sudhir ; Wirbelauer, Christiane ; Kaut, Johannes ; Terranova, Rémi ; Hoerner, Leslie ; Mielke, Christian ; Boege, Fritz ; Murr, Rabih ; Peters, Antoine H F M ; Barde, Yves-Alain ; Schübeler, Dirk. / Target genes of Topoisomerase IIβ regulate neuronal survival and are defined by their chromatin state. Proceedings of the National Academy of Sciences. 2012. pp. E934-43 (Proceedings of the National Academy of Sciences).
@inbook{2885e87448bb49b89e893cb668d532c0,
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.",
author = "Tiwari, {Vijay K} and Lukas Burger and Vassiliki Nikoletopoulou and Ruben Deogracias and Sudhir Thakurela and Christiane Wirbelauer and Johannes Kaut and R{\'e}mi Terranova and Leslie Hoerner and Christian Mielke and Fritz Boege and Rabih Murr and Peters, {Antoine H F M} and Yves-Alain Barde and Dirk Sch{\"u}beler",
year = "2012",
doi = "10.1073/pnas.1119798109",
language = "English",
isbn = "1091-6490 (Electronic)\r0027-8424 (Linking)",
series = "Proceedings of the National Academy of Sciences",
pages = "E934--43",
booktitle = "Proceedings of the National Academy of Sciences",

}

Tiwari, VK, Burger, L, Nikoletopoulou, V, Deogracias, R, Thakurela, S, Wirbelauer, C, Kaut, J, Terranova, R, Hoerner, L, Mielke, C, Boege, F, Murr, R, Peters, AHFM, Barde, Y-A & Schübeler, D 2012, Target genes of Topoisomerase IIβ regulate neuronal survival and are defined by their chromatin state. in Proceedings of the National Academy of Sciences. Proceedings of the National Academy of Sciences, vol. 109, pp. E934-43. https://doi.org/10.1073/pnas.1119798109

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, Rémi; Hoerner, Leslie; Mielke, Christian; Boege, Fritz; Murr, Rabih; Peters, Antoine H F M; Barde, Yves-Alain; Schübeler, Dirk.

Proceedings of the National Academy of Sciences. 2012. p. E934-43 (Proceedings of the National Academy of Sciences; Vol. 109).

Research output: Chapter in Book/Report/Conference proceedingChapter

TY - CHAP

T1 - Target genes of Topoisomerase IIβ regulate neuronal survival and are defined by their chromatin state.

AU - Tiwari, Vijay K

AU - Burger, Lukas

AU - Nikoletopoulou, Vassiliki

AU - Deogracias, Ruben

AU - Thakurela, Sudhir

AU - Wirbelauer, Christiane

AU - Kaut, Johannes

AU - Terranova, Rémi

AU - Hoerner, Leslie

AU - Mielke, Christian

AU - Boege, Fritz

AU - Murr, Rabih

AU - Peters, Antoine H F M

AU - Barde, Yves-Alain

AU - Schübeler, Dirk

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

UR - http://www.pnas.org/cgi/doi/10.1073/pnas.1119798109%5Cnpapers3://publication/doi/10.1073/pnas.1119798109

UR - http://www.mendeley.com/research/target-genes-topoisomerase-ii%CE%B2-regulate-neuronal-survival-defined-chromatin-state

U2 - 10.1073/pnas.1119798109

DO - 10.1073/pnas.1119798109

M3 - Chapter

C2 - 22474351

SN - 1091-6490 (Electronic)\r0027-8424 (Linking)

T3 - Proceedings of the National Academy of Sciences

SP - E934-43

BT - Proceedings of the National Academy of Sciences

ER -

Tiwari VK, Burger L, Nikoletopoulou V, Deogracias R, Thakurela S, Wirbelauer C 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. p. E934-43. (Proceedings of the National Academy of Sciences). https://doi.org/10.1073/pnas.1119798109