DNA Double-Strand Breaks Are a Critical Regulator of Fear Memory Reconsolidation
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 hip...
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doaj-accae08d911043daa65a1402157762a52020-11-27T08:12:04ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-11-01218995899510.3390/ijms21238995DNA Double-Strand Breaks Are a Critical Regulator of Fear Memory ReconsolidationShaghayegh Navabpour0Jessie Rogers1Taylor McFadden2Timothy J. Jarome3Fralin Biomedical Research Institute, Translational Biology, Medicine & Health, Virginia Polytechnic Institute and State University, Roanoke, VA 24016, USADepartment of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USADepartment of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USAFralin Biomedical Research Institute, Translational Biology, Medicine & Health, Virginia Polytechnic Institute and State University, Roanoke, VA 24016, USANumerous 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 <i>Npas4</i>, but not <i>c-fos</i>, 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 <i>Npas4</i> 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.https://www.mdpi.com/1422-0067/21/23/8995epigenetichistone methylationDNA double-strand breaksmemoryreconsolidationretrieval |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shaghayegh Navabpour Jessie Rogers Taylor McFadden Timothy J. Jarome |
spellingShingle |
Shaghayegh Navabpour Jessie Rogers Taylor McFadden Timothy J. Jarome DNA Double-Strand Breaks Are a Critical Regulator of Fear Memory Reconsolidation International Journal of Molecular Sciences epigenetic histone methylation DNA double-strand breaks memory reconsolidation retrieval |
author_facet |
Shaghayegh Navabpour Jessie Rogers Taylor McFadden Timothy J. Jarome |
author_sort |
Shaghayegh Navabpour |
title |
DNA Double-Strand Breaks Are a Critical Regulator of Fear Memory Reconsolidation |
title_short |
DNA Double-Strand Breaks Are a Critical Regulator of Fear Memory Reconsolidation |
title_full |
DNA Double-Strand Breaks Are a Critical Regulator of Fear Memory Reconsolidation |
title_fullStr |
DNA Double-Strand Breaks Are a Critical Regulator of Fear Memory Reconsolidation |
title_full_unstemmed |
DNA Double-Strand Breaks Are a Critical Regulator of Fear Memory Reconsolidation |
title_sort |
dna double-strand breaks are a critical regulator of fear memory reconsolidation |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-11-01 |
description |
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 <i>Npas4</i>, but not <i>c-fos</i>, 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 <i>Npas4</i> 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. |
topic |
epigenetic histone methylation DNA double-strand breaks memory reconsolidation retrieval |
url |
https://www.mdpi.com/1422-0067/21/23/8995 |
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