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.
authors.affiliation: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Ram
authors.initials: R
authors.lastname: Madabhushi
authors.affiliation: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Gao
authors.affiliation: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA.
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Pfenning
authors.affiliation: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Pan
authors.affiliation: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Satoko
authors.initials: S
authors.lastname: Yamakawa
authors.affiliation: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Jinsoo
authors.initials: J
authors.lastname: Seo
authors.affiliation: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Rueda
authors.affiliation: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Trongha X
authors.initials: TX
authors.lastname: Phan
authors.affiliation: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Hidekuni
authors.initials: H
authors.lastname: Yamakawa
authors.affiliation: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Ping-Chieh
authors.initials: PC
authors.lastname: Pao
authors.affiliation: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Stott
authors.affiliation: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA.
authors.forename: Elizabeta
authors.initials: E
authors.lastname: Gjoneska
authors.affiliation: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Alexi
authors.initials: A
authors.lastname: Nott
authors.affiliation: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Sukhee
authors.initials: S
authors.lastname: Cho
authors.affiliation: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA.
authors.forename: Manolis
authors.initials: M
authors.lastname: Kellis
authors.affiliation: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA. Electronic address: lhtsai@mit.edu.
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D000076246:CCCTC-Binding Factor; D053903:DNA Breaks, Double-Stranded; D004250:DNA Topoisomerases, Type II / Q000032:analysis / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000235:genetics; D005047:Etoposide / Q000494:pharmacology; D005786:Gene Expression Regulation; D016762:Genes, fos; D055106:Genome-Wide Association Study; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000076246:CCCTC-Binding Factor; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; D005047:Etoposide; D012097:Repressor Proteins; C000619698:Ctcf protein, mouse; C486109:Egr1 protein, mouse; C533005:Npas4 protein, mouse