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

Cell
Authors
Keywords
Abstract

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.

Year of Publication
2015
Journal
Cell
Volume
161
Issue
7
Pages
1592-605
Date Published
2015 Jun 18
ISSN
1097-4172
URL
DOI
10.1016/j.cell.2015.05.032
PubMed ID
26052046
PubMed Central ID
PMC4886855
Links
Grant list
R01 HG004037 / HG / NHGRI NIH HHS / United States
R01HG004037-07 / HG / NHGRI NIH HHS / United States
U01 HG007610 / HG / NHGRI NIH HHS / United States
RC1 HG005334 / HG / NHGRI NIH HHS / United States
R01 AG046174 / AG / NIA NIH HHS / United States
R01AG046174 / AG / NIA NIH HHS / United States
RC1HG005334 / HG / NHGRI NIH HHS / United States