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

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Vijay K Tiwari1, Lukas Burger, Vassiliki Nikoletopoulou

  • 1Friedrich Miescher Institute for Biomedical Research, CH-4058 Basel, Switzerland. v.tiwari@imb-mainz.de

Proceedings of the National Academy of Sciences of the United States of America
|April 5, 2012
PubMed

Insights

Topoisomerase IIβ (Top2β) targets regulatory DNA regions in postmitotic neurons, controlling gene expression critical for neuronal survival. Its deficiency leads to neuronal death via Ngfr p75 upregulation.

Area of Science:

  • Genetics
  • Neuroscience
  • Molecular Biology

Background:

  • Topoisomerases are crucial for DNA replication in dividing cells.
  • The roles of topoisomerases in postmitotic cells, particularly neurons, are not well understood.

Purpose of the Study:

  • To investigate the function and genomic targets of topoisomerases in postmitotic neurons.
  • To elucidate the role of Topoisomerase IIβ (Top2β) in neuronal differentiation and survival.

Main Methods:

  • Genome-scale location analysis (ChIP-seq) in stem cell-derived postmitotic neurons.
  • Analysis of gene expression and chromatin accessibility in Top2β deficient neurons.
  • Investigating the impact of Top2β deficiency on neuronal survival and specific gene regulation.

Main Results:

  • A switch from Topoisomerase IIα (Top2α) to Top2β expression occurs during neuronal differentiation.
  • Top2β binds to regulatory regions, primarily promoters, marked by histone H3 lysine 4 methylation in postmitotic neurons.
  • Top2β deficiency alters transcription and chromatin accessibility, leading to premature neuronal death due to Ngfr p75 upregulation.

Conclusions:

  • Top2β is targeted to specific genomic regulatory regions in postmitotic neurons.
  • Top2β plays a critical role in maintaining the transcriptional program for neuronal longevity.
  • Dysregulation of Top2β contributes to neuronal degeneration through aberrant gene expression, such as Ngfr p75.

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