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Updated: Oct 25, 2026

Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers
Published on: September 20, 2018
Programmed DNA breaks drive chromatin reconfiguration and facilitate transcriptional potentiation at neuronal early
Lance Heady1, Kelli D Fenelon1, Ilse Delint-Ramirez1
1Departments of Psychiatry, Neuroscience, and Cell Biology, Dallas, TX, USA; The Peter O' Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Abstract:
Neuronal activity causes topoisomerase IIβ (TOP2B) to form DNA double-strand breaks (DSBs) within the promoters of early response genes (ERGs), such as Fos and Npas4. TOP2B-mediated DSBs facilitate ERG transcription, yet how this occurs is unclear. Using circular chromosome conformation capture (4C-seq), we report here that DSB formation is sufficient to emulate contact profiles observed at the promoters of Fos and Npas4 following neuronal stimulation, including elevated interactions with their cognate enhancers. Despite their purported risk, recurrent DSB cycles progressively potentiate ERG induction in mouse cortical neurons and HEK293T cells, evoking the effects of transcriptional memory. Potentiated ERG inducibility following recurrent DSBs persists through intervening cell cycles, occurs even when DNA repair is likely mutagenic, and correlates with a substantial loss of cis- and a gain of trans-, chromosomal interactions with ERG promoters. Together, these results reveal how activity-induced DSBs impact transcription by regulating chromatin dynamics at ERG promoters.
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