TY - JOUR
T1 - Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes
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
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
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.
UR - http://www.scopus.com/inward/record.url?scp=84931577486&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2015.05.032
DO - 10.1016/j.cell.2015.05.032
M3 - Article
C2 - 26052046
AN - SCOPUS:84931577486
SN - 0092-8674
VL - 161
SP - 1592
EP - 1605
JO - Cell
JF - Cell
IS - 7
ER -