Programmed DNA breaks drive chromatin reconfiguration and facilitate transcriptional potentiation at neuronal early response genes
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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BibTeX
@article{heady2026programmed,
title = {{Programmed DNA breaks drive chromatin reconfiguration and facilitate transcriptional potentiation at neuronal early response genes}},
author = {Lance Heady and Kelli D. Fenelon and Ilse Delint-Ramirez and Richard Rueda and Amir Segev and Krystal G. Morton and Sandra Fajardo Briseno and Ram Madabhushi},
journal = {Cell Reports},
year = {2026},
month = oct,
doi = {10.1016/j.celrep.2026.118186},
url = {https://linkinghub.elsevier.com/retrieve/pii/S2211124726012659},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Programmed DNA breaks drive chromatin reconfiguration and facilitate transcriptional potentiation at neuronal early response genes
AU - Lance Heady
AU - Kelli D. Fenelon
AU - Ilse Delint-Ramirez
AU - Richard Rueda
AU - Amir Segev
AU - Krystal G. Morton
AU - Sandra Fajardo Briseno
AU - Ram Madabhushi
PY - 2026
DA - 2026/10/30
JO - Cell Reports
DO - 10.1016/j.celrep.2026.118186
UR - https://linkinghub.elsevier.com/retrieve/pii/S2211124726012659
AB - 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.
SN - 2211-1247
ER -