Programmed DNA breaks drive chromatin reconfiguration and facilitate transcriptional potentiation at neuronal early response genes
Year: 2026
Type: article
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.
Source: Cell Reports
Institution: The University of Texas Southwestern Medical Center
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
Awards: Mechanisms of Disease & Translational Science, The Cellular and Systems Biology of Sleep and Circadian Rhythms Training Program, Mechanisms regulating the formation and repair of neuronal activity-induced DNA breaks in vivo and their effects on chromatin architecture and neuronal physiology, The impact of stress-induced DNA breaks on chromatin structure, gene activity, and neuron function
OpenAlex ID: W7223180691