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Article

DNA Double-Strand Breaks Are a Critical Regulator of Fear Memory Reconsolidation

1
Fralin Biomedical Research Institute, Translational Biology, Medicine & Health, Virginia Polytechnic Institute and State University, Roanoke, VA 24016, USA
2
Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
3
Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
4
School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(23), 8995; https://doi.org/10.3390/ijms21238995
Received: 13 November 2020 / Revised: 23 November 2020 / Accepted: 23 November 2020 / Published: 26 November 2020
(This article belongs to the Special Issue Molecular Mechanisms of Memory Formation and Modification)
Numerous studies have shown that following retrieval, a previously consolidated memory requires increased transcriptional regulation in order to be reconsolidated. Previously, it was reported that histone H3 lysine-4 trimethylation (H3K4me3), a marker of active transcription, is increased in the hippocampus after the retrieval of contextual fear memory. However, it is currently unknown how this epigenetic mark is regulated during the reconsolidation process. Furthermore, though recent evidence suggests that neuronal activity triggers DNA double-strand breaks (DSBs) in some early-response genes, it is currently unknown if DSBs contribute to the reconsolidation of a memory following retrieval. Here, using chromatin immunoprecipitation (ChIP) analyses, we report a significant overlap between DSBs and H3K4me3 in area CA1 of the hippocampus during the reconsolidation process. We found an increase in phosphorylation of histone H2A.X at serine 139 (H2A.XpS139), a marker of DSB, in the Npas4, but not c-fos, promoter region 5 min after retrieval, which correlated with increased H3K4me3 levels, suggesting that the two epigenetic marks may work in concert during the reconsolidation process. Consistent with this, in vivo siRNA-mediated knockdown of topoisomerase II β, the enzyme responsible for DSB, prior to retrieval, reduced Npas4 promoter-specific H2A.XpS139 and H3K4me3 levels and impaired long-term memory, indicating an indispensable role of DSBs in the memory reconsolidation process. Collectively, our data propose a novel mechanism for memory reconsolidation through increases in epigenetic-mediated transcriptional control via DNA double-strand breaks. View Full-Text
Keywords: epigenetic; histone methylation; DNA double-strand breaks; memory; reconsolidation; retrieval; hippocampus epigenetic; histone methylation; DNA double-strand breaks; memory; reconsolidation; retrieval; hippocampus
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MDPI and ACS Style

Navabpour, S.; Rogers, J.; McFadden, T.; Jarome, T.J. DNA Double-Strand Breaks Are a Critical Regulator of Fear Memory Reconsolidation. Int. J. Mol. Sci. 2020, 21, 8995. https://doi.org/10.3390/ijms21238995

AMA Style

Navabpour S, Rogers J, McFadden T, Jarome TJ. DNA Double-Strand Breaks Are a Critical Regulator of Fear Memory Reconsolidation. International Journal of Molecular Sciences. 2020; 21(23):8995. https://doi.org/10.3390/ijms21238995

Chicago/Turabian Style

Navabpour, Shaghayegh, Jessie Rogers, Taylor McFadden, and Timothy J. Jarome. 2020. "DNA Double-Strand Breaks Are a Critical Regulator of Fear Memory Reconsolidation" International Journal of Molecular Sciences 21, no. 23: 8995. https://doi.org/10.3390/ijms21238995

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