The mechanisms behind age-related memory loss are not currently understood. This research establishes that disturbances in memory in the aging brain of the mouse are associated with altered hippocampal chromatin plasticity. During learning, aged mice show a deregulation of histone H4 lysine 12 (H4K12) acetylation, and fail to initiate a gene expression program associated with memory consolidation. When physiological H4K12 acetylation is restored, the expression of learning-induced genes is reinstated, and cognitive abilities are recovered. Deregulated H4K12 acetylation may be useful as an early biomarker for memory impairment during aging.
Altered histone acetylation is associated with age-dependent memory impairment in mice
1. Figure 4. Heat map of differentially expressed genes.
Formin-2 Gene
• 3-month old mice had higher levels of the protein.
• Knocking out the gene produces mice with cognitive
impairments.
Histone deacetylaces (Figure 5)
• Hippocampal injections restore H4K12 acetylation, gene-
expression, and learning behavior in 16-month old mice
Figure 1. Relationship of DNA, histones, and nucleosomes.
Acetylation in fear conditioned mice (Fig. 3)
• 16-month old mice fail to upregulate H4K12 acetylation after 1 hour.
Figure 3. Impaired learning and memory in 16-month old mice correlates
with deregulated H4K12 acetylation.
Differentially Expressed Genes (Figure 4)
• In 3-month old mice: 1980 genes are upregulated, 449 are
downregulated [1539 of which are linked to associative learning, and
are implicated in transcription, protein modification, or intracellular
signaling].
• In 16-month old mice, 6 genes are differentially expressed.
Altered Histone Acetylation Is Associated with Age-Dependent Memory Impairment in Mice
Andre Fischer et al.; Presented by Charlotte Chaze
Introduction
The mechanisms behind age-related memory loss are not
currently understood. This research establishes that
disturbances in memory in the aging brain of the mouse are
associated with altered hippocampal chromatin plasticity. During
learning, aged mice show a deregulation of histone H4 lysine 12
(H4K12) acetylation, and fail to initiate a gene expression
program associated with memory consolidation. When
physiological H4K12 acetylation is restored, the expression of
learning-induced genes is reinstated, and cognitive abilities are
recovered. Deregulated H4K12 acetylation may be useful as an
early biomarker for memory impairment during aging.
Experimental Procedures
Cognitive Tests
• 3-, 8-, and 16-month-old mice are subjected to contextual
fear conditioning (FC) and the Morris water maze to
determine an age at which cognitive impairment is first
manifested.
Histone Acetylation
• To test whether memory impairment is correlated with altered
chromatin plasticity, quantitative immunoblot analysis is used
to find whether hippocampal histone acetylation differs
between 3- and 16-month old naïve mice, and between 3-
and 16-month old FC mice.
Gene Expression Changes
• To find whether H4K12 acetylation has an impact on learning-
induced gene expression, the entire hippocampal gene
expressions for 3- and 16-month old mice are compared
during memory consolidation.
• The Formin-2 gene is knocked out to test whether the lack of
learning-induced gene expression is linked to deregulated
H4K12 acetylation associated with transcriptional elongation
of upregulated genes.
• To find if H4K12 acetylation can restore learning-induced
gene expression, mice are injected with a histone
deacetylase inhibitor, suberoylanilide hydroxamic acid
(SAHA)
Results
Cognitive functions
• In water maze, there’s a higher escape latency in 16-month
old mice.
• In FC, there is significantly less freezing behavior in 16-
month old mice.
Acetylation under normal conditions (Fig. 1 & 2)
• Lysine residues are acetylated on histones H3 and H4.
References
Fischer, A. et al. Altered Histone Acetylation is Associated
with Age-Dependent Memory Impairment in Mice. Science
2010, 328, 753-756.
Stilling, R. & Fischer, A. The Role of Histone Acetylation in
Age-Associated Memory Impairment and Alzheimer’s
Disease. Neurobiol. of Learning and Memory 2011, 96, 19-
26.
Chromatin illustrations by Richard Wheeler, used with
permission. [http://www.richardwheeler.net]
Figure 2. These two
nucleosomal histones can
be acetylated on different
lysine residues (K). The N-
terminal tails protrude from
the core nucleosome and
are accessible to enzymatic
modifications.
Conclusion
• Alterations in learning-dependent acetylation at H4K12
may be an early biomarker of memory impairment during
aging.
• Restoring histone acetylation can restore memory
consolidation and learning-induced changes in gene
expression that are ordinarily altered in aging brains.
Figure 5.
Effects of
HDAC
inhibitor
(SAHA).
![Figure 4. Heat map of differentially expressed genes.
Formin-2 Gene
• 3-month old mice had higher levels of the protein.
• Knocking out the gene produces mice with cognitive
impairments.
Histone deacetylaces (Figure 5)
• Hippocampal injections restore H4K12 acetylation, gene-
expression, and learning behavior in 16-month old mice
Figure 1. Relationship of DNA, histones, and nucleosomes.
Acetylation in fear conditioned mice (Fig. 3)
• 16-month old mice fail to upregulate H4K12 acetylation after 1 hour.
Figure 3. Impaired learning and memory in 16-month old mice correlates
with deregulated H4K12 acetylation.
Differentially Expressed Genes (Figure 4)
• In 3-month old mice: 1980 genes are upregulated, 449 are
downregulated [1539 of which are linked to associative learning, and
are implicated in transcription, protein modification, or intracellular
signaling].
• In 16-month old mice, 6 genes are differentially expressed.
Altered Histone Acetylation Is Associated with Age-Dependent Memory Impairment in Mice
Andre Fischer et al.; Presented by Charlotte Chaze
Introduction
The mechanisms behind age-related memory loss are not
currently understood. This research establishes that
disturbances in memory in the aging brain of the mouse are
associated with altered hippocampal chromatin plasticity. During
learning, aged mice show a deregulation of histone H4 lysine 12
(H4K12) acetylation, and fail to initiate a gene expression
program associated with memory consolidation. When
physiological H4K12 acetylation is restored, the expression of
learning-induced genes is reinstated, and cognitive abilities are
recovered. Deregulated H4K12 acetylation may be useful as an
early biomarker for memory impairment during aging.
Experimental Procedures
Cognitive Tests
• 3-, 8-, and 16-month-old mice are subjected to contextual
fear conditioning (FC) and the Morris water maze to
determine an age at which cognitive impairment is first
manifested.
Histone Acetylation
• To test whether memory impairment is correlated with altered
chromatin plasticity, quantitative immunoblot analysis is used
to find whether hippocampal histone acetylation differs
between 3- and 16-month old naïve mice, and between 3-
and 16-month old FC mice.
Gene Expression Changes
• To find whether H4K12 acetylation has an impact on learning-
induced gene expression, the entire hippocampal gene
expressions for 3- and 16-month old mice are compared
during memory consolidation.
• The Formin-2 gene is knocked out to test whether the lack of
learning-induced gene expression is linked to deregulated
H4K12 acetylation associated with transcriptional elongation
of upregulated genes.
• To find if H4K12 acetylation can restore learning-induced
gene expression, mice are injected with a histone
deacetylase inhibitor, suberoylanilide hydroxamic acid
(SAHA)
Results
Cognitive functions
• In water maze, there’s a higher escape latency in 16-month
old mice.
• In FC, there is significantly less freezing behavior in 16-
month old mice.
Acetylation under normal conditions (Fig. 1 & 2)
• Lysine residues are acetylated on histones H3 and H4.
References
Fischer, A. et al. Altered Histone Acetylation is Associated
with Age-Dependent Memory Impairment in Mice. Science
2010, 328, 753-756.
Stilling, R. & Fischer, A. The Role of Histone Acetylation in
Age-Associated Memory Impairment and Alzheimer’s
Disease. Neurobiol. of Learning and Memory 2011, 96, 19-
26.
Chromatin illustrations by Richard Wheeler, used with
permission. [http://www.richardwheeler.net]
Figure 2. These two
nucleosomal histones can
be acetylated on different
lysine residues (K). The N-
terminal tails protrude from
the core nucleosome and
are accessible to enzymatic
modifications.
Conclusion
• Alterations in learning-dependent acetylation at H4K12
may be an early biomarker of memory impairment during
aging.
• Restoring histone acetylation can restore memory
consolidation and learning-induced changes in gene
expression that are ordinarily altered in aging brains.
Figure 5.
Effects of
HDAC
inhibitor
(SAHA).](https://image.slidesharecdn.com/alteredhistoneacetylation-140702005019-phpapp01/85/Altered-histone-acetylation-is-associated-with-age-dependent-memory-impairment-in-mice-1-320.jpg)
