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

Ram Madabhushi; Fan Gao; Andreas R. Pfenning; Ling Pan; Satoko Yamakawa; Jinsoo Seo; Richard Rueda; Trongha X. Phan; Hidekuni Yamakawa; Ping Chieh Pao; Ryan T. Stott; Elizabeta Gjoneska; Alexi Nott; Sukhee Cho; Manolis Kellis; Li Huei Tsai

doi:10.1016/j.cell.2015.05.032

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

Ram Madabhushi, Fan Gao, Andreas R. Pfenning, Ling Pan, Satoko Yamakawa, Jinsoo Seo, Richard Rueda, Trongha X. Phan, Hidekuni Yamakawa, Ping Chieh Pao, Ryan T. Stott, Elizabeta Gjoneska, Alexi Nott, Sukhee Cho, Manolis Kellis, Li Huei Tsai

Research output: Contribution to journal › Article › peer-review

468 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1592-1605
Number of pages	14
Journal	Cell
Volume	161
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2015.05.032
State	Published - Jun 18 2015

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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title = "Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes",

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.",

author = "Ram Madabhushi and Fan Gao and Pfenning, {Andreas R.} and Ling Pan and Satoko Yamakawa and Jinsoo Seo and Richard Rueda and Phan, {Trongha X.} and Hidekuni Yamakawa and Pao, {Ping Chieh} and Stott, {Ryan T.} and Elizabeta Gjoneska and Alexi Nott and Sukhee Cho and Manolis Kellis and Tsai, {Li Huei}",

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year = "2015",

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doi = "10.1016/j.cell.2015.05.032",

language = "English (US)",

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AU - Madabhushi, Ram

AU - Gao, Fan

AU - Pfenning, Andreas R.

AU - Pan, Ling

AU - Yamakawa, Satoko

AU - Seo, Jinsoo

AU - Rueda, Richard

AU - Phan, Trongha X.

AU - Yamakawa, Hidekuni

AU - Pao, Ping Chieh

AU - Stott, Ryan T.

AU - Gjoneska, Elizabeta

AU - Nott, Alexi

AU - Cho, Sukhee

AU - Kellis, Manolis

AU - Tsai, Li Huei

PY - 2015/6/18

Y1 - 2015/6/18

N2 - 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.

AB - 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.

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

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