Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes

Cell. 2015 Jun 18;161(7):1592-605. doi: 10.1016/j.cell.2015.05.032. Epub 2015 Jun 4.


Neuronal activity causes the rapid expression of immediate early genes that are crucial for experience-driven changes to synapses, learning, and memory. Here, using both molecular and genome-wide next-generation sequencing methods, we report that neuronal activity stimulation triggers the formation of DNA double strand breaks (DSBs) in the promoters of a subset of early-response genes, including Fos, Npas4, and Egr1. Generation of targeted DNA DSBs within Fos and Npas4 promoters is sufficient to induce their expression even in the absence of an external stimulus. Activity-dependent DSB formation is likely mediated by the type II topoisomerase, Topoisomerase IIβ (Topo IIβ), and knockdown of Topo IIβ attenuates both DSB formation and early-response gene expression following neuronal stimulation. Our results suggest that DSB formation is a physiological event that rapidly resolves topological constraints to early-response gene expression in neurons.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • CCCTC-Binding Factor
  • DNA Breaks, Double-Stranded*
  • DNA Topoisomerases, Type II / analysis
  • DNA Topoisomerases, Type II / metabolism
  • DNA-Binding Proteins / analysis
  • DNA-Binding Proteins / metabolism
  • Early Growth Response Protein 1 / genetics
  • Etoposide / pharmacology
  • Gene Expression Regulation
  • Genes, fos
  • Genome-Wide Association Study
  • Mice
  • Neurons / metabolism*
  • Repressor Proteins / metabolism
  • Transcriptome / drug effects


  • Basic Helix-Loop-Helix Transcription Factors
  • CCCTC-Binding Factor
  • Ctcf protein, mouse
  • DNA-Binding Proteins
  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Npas4 protein, mouse
  • Repressor Proteins
  • Etoposide
  • DNA Topoisomerases, Type II

Associated data

  • GEO/GSE61887