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

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...

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Bibliographic Details
Published in:Cell 2015-06, Vol.161 (7), p.1592-1605
Main Authors: Madabhushi, Ram, Gao, Fan, Pfenning, Andreas R., Pan, Ling, Yamakawa, Satoko, Seo, Jinsoo, Rueda, Richard, Phan, Trongha X., Yamakawa, Hidekuni, Pao, Ping-Chieh, Stott, Ryan T., Gjoneska, Elizabeta, Nott, Alexi, Cho, Sukhee, Kellis, Manolis, Tsai, Li-Huei
Format: Article
Language:English
Subjects:
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
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Summary: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. [Display omitted] [Display omitted] •Neuronal activity causes the formation of DNA double strand breaks (DSBs)•Activity-induced DSBs form within the promoters of a subset of early-response genes•Topoisomerase IIβ is necessary for activity-induced DSB formation•Activity-induced DSBs facilitate the expression of early-response genes in neurons The formation of activity-induced DNA double strand breaks within promoter regions is required for transcription of a subset of neuronal early-response genes that are crucial for experience-driven synaptic changes associated with learning and memory.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2015.05.032