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

Authors :
Navabpour S
Rogers J
McFadden T
Jarome TJ
Source :
International journal of molecular sciences [Int J Mol Sci] 2020 Nov 26; Vol. 21 (23). Date of Electronic Publication: 2020 Nov 26.
Publication Year :
2020

Abstract

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.

Details

Language :
English
ISSN :
1422-0067
Volume :
21
Issue :
23
Database :
MEDLINE
Journal :
International journal of molecular sciences
Publication Type :
Academic Journal
Accession number :
33256213
Full Text :
https://doi.org/10.3390/ijms21238995