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 journalArticle

265 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. PaperClip

Original languageEnglish (US)
Pages (from-to)1592-1605
Number of pages14
JournalCell
Volume161
Issue number7
DOIs
StatePublished - Jun 18 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Madabhushi, R., Gao, F., Pfenning, A. R., Pan, L., Yamakawa, S., Seo, J., Rueda, R., Phan, T. X., Yamakawa, H., Pao, P. C., Stott, R. T., Gjoneska, E., Nott, A., Cho, S., Kellis, M., & Tsai, L. H. (2015). Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes. Cell, 161(7), 1592-1605. https://doi.org/10.1016/j.cell.2015.05.032