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Increase in hippocampal histone H3K9me3 is negatively correlated with memory in old male mice

  • Akanksha Kushwaha
  • Mahendra Kumar ThakurEmail author
Research Article

Abstract

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.

Graphic abstract

Diagram here represents that during aging, there is increase in expression of SUV39H1. Such increased enzyme upregulates global and gene specific methylation in hippocampus of old male mice. H3K9me3 level increases at the promoter of neuronal IEGs leading to heterochromatisation and hence decrease in their expression and ultimately decline in memory during aging.

Keywords

Aging IEGs H3K9me3 SUV39H1 Memory Hippocampus 

Notes

Acknowledgements

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.

Supplementary material

10522_2019_9850_MOESM1_ESM.jpg (629 kb)
Supplementary material 1—ChIP validation using anti-IgG and anti-H3K9me3 antibody (JPEG 629 kb)
10522_2019_9850_MOESM2_ESM.pdf (234 kb)
Supplementary material 2 (PDF 234 kb)

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Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Biochemistry and Molecular Biology Laboratory, Department of ZoologyBanaras Hindu UniversityVaranasiIndia

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