Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes
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Kellis_Activity-induced dna.pdf
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2.96 MB
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Author(s)
Madabhushi, Ram
Pfenning, Andreas R.
Gao, Fan
Pan, Ling
Yamakawa, Satoko
Seo, Jinsoo
Rueda IV, Richard
Phan, Trongha
Yamakawa, Hidekuni
Pao, Ping-Chieh
Date Issued
June 2015
Journal
Cell
Publisher
Elsevier
Citation
Madabhushi, Ram et al. “Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes.” Cell 161, 7 (June 2015): 1592–1605 © 2015 Elsevier Inc
Version
Author's final manuscript
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.
MIT Department
Broad Institute of MIT and Harvard
Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
Picower Institute for Learning and Memory
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.cell.2015.05.032
