Increase in hippocampal histone H3K9me3 is negatively correlated with memory in old male mice
With advancing age, memory declines through different mechanisms including dysregulation of expression of synaptic plasticity genes in hippocampus. Increasing evidences suggest that these synaptic plasticity genes are regulated through epigenetic modifications. Recently we have reported that the neuronal immediate early genes (IEGs) are regulated by DNA methylation and histone acetylation, and their expression is downregulated in the hippocampus of old male mice, which subsequently results in decline of memory. These modifications do not work in isolation but act synergistically and lead to distinct regulation of gene expression. Therefore, in the present study, we have explored whether these genes are also regulated by histone methylation and this has any correlation with memory decline during aging. This study for the first time reports involvement of H3K9me3 in the regulation of neuronal IEGs during aging. Using novel object recognition and Y-maze test, the recognition and spatial memory was checked in male mice of different ages and it was found to decline in old. We have examined the expression of H3K9me3 specific histone methyltransferases and noted that only SUV39H1 (suppressor of variegation 3–9 homolog 1) increased significantly in old. Also the global H3K9me3 level was high in the hippocampus of old male mice. Further, chromatin immunoprecipitation assay revealed rise in H3K9me3 level at the promoter of IEGs in old as compared to young male mice. The immunofluorescence analysis also showed varying pattern of H3K9me3 expression in different subregions of hippocampus with aging. These findings showed negative correlation of increase in hippocampal histone H3K9me3 with memory decline in old male mice.
KeywordsAging IEGs H3K9me3 SUV39H1 Memory Hippocampus
The authors acknowledge the use of real-time PCR and Confocal microscope facility at the Interdisciplinary School of Life Sciences, Banaras Hindu University. Akanksha Kushwaha acknowledges Council of Scientific & Industrial Research (CSIR), India for Junior Research Fellowship. The work was financially supported by University Grants Commission, Indian Council of Medical Research (5/4-5/153/Neuro/2015-NCD-I), and Department of Science & Technology, India (EMR/2015/002178) to MKT.
Compliance with ethical standards
Conflict of interest
Authors declare no conflict of interest.
- Fahlstrom A, Yu Q, Ulfhake B (2011) Behavioral changes in aging female C57BL/6 mice. Neurobiol Aging 32(10):1868–1880. https://doi.org/10.1016/j.neurobiolaging.2009.11.003 CrossRefPubMedGoogle Scholar
- Gupta-Agarwal S, Franklin AV, Deramus T et al (2012) G9a/GLP histone lysine dimethyltransferase complex activity in the hippocampus and the entorhinal cortex is required for gene activation and silencing during memory consolidation. J Neurosci 32(16):5440–5453. https://doi.org/10.1523/JNEUROSCI.0147-12.2012 CrossRefPubMedPubMedCentralGoogle Scholar
- Penner MR, Roth TL, Chawla MK et al (2011) Age-related changes in Arc transcription and DNA methylation within the hippocampus. Neurobiol Aging 32(12):2198–2210. https://doi.org/10.1016/j.neurobiolaging.2010.01.009 CrossRefPubMedGoogle Scholar
- Reolon GK, Maurmann N, Werenicz A et al (2011) Posttraining systemic administration of the histone deacetylase inhibitor sodium butyrate ameliorates aging-related memory decline in rats. Behav Brain Res 221(1):329–332. https://doi.org/10.1016/j.bbr.2011.03.033 CrossRefPubMedPubMedCentralGoogle Scholar
- Villeneuve LM, Kato M, Reddy MA (2010) Enhanced levels of microRNA-125b in vascular smooth muscle cells of diabetic db/db mice lead to increased inflammatory gene expression by targeting the histone methyltransferase Suv39h1. Diabetes 59(11):2904–2915. https://doi.org/10.2337/db10-0208 CrossRefPubMedPubMedCentralGoogle Scholar
- Webb WM, Sanchez RG, Perez G et al (2017) Dynamic association of epigenetic H3K4me3 and DNA 5hmC marks in the dorsal hippocampus and anterior cingulate cortex following reactivation of a fear memory. Neurobiol Learn Mem 142(Pt A):66–78. https://doi.org/10.1016/j.nlm.2017.02.010 CrossRefPubMedGoogle Scholar