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An epigenetic hypothesis of aging-related cognitive dysfunction.

Penner MR, Roth TL, Barnes CA, Sweatt JD - Front Aging Neurosci (2010)

Bottom Line: These mechanisms, in turn, result in alterations in specific patterns of gene expression.Here we focus on this theme, reviewing current knowledge concerning epigenetic molecular mechanisms, as well as recent results suggesting disruption of plasticity and memory formation during aging.Finally, several open questions will be discussed that we believe will fuel experimental discovery.

View Article: PubMed Central - PubMed

Affiliation: Arizona Research Laboratories Division of Neural Systems, Memory and Aging and Evelyn F. McKnight Brain Institute, University of Arizona Tucson, AZ, USA.

ABSTRACT
This brief review will focus on a new hypothesis for the role of epigenetic mechanisms in aging-related disruptions of synaptic plasticity and memory. Epigenetics refers to a set of potentially self-perpetuating, covalent modifications of DNA and post-translational modifications of nuclear proteins that produce lasting alterations in chromatin structure. These mechanisms, in turn, result in alterations in specific patterns of gene expression. Aging-related memory decline is manifest prominently in declarative/episodic memory and working memory, memory modalities anatomically based largely in the hippocampus and prefrontal cortex, respectively. The neurobiological underpinnings of age-related memory deficits include aberrant changes in gene transcription that ultimately affect the ability of the aged brain to be "plastic". The molecular mechanisms underlying these changes in gene transcription are not currently known, but recent work points toward a potential novel mechanism, dysregulation of epigenetic mechanisms. This has led us to hypothesize that dysregulation of epigenetic control mechanisms and aberrant epigenetic "marks" drive aging-related cognitive dysfunction. Here we focus on this theme, reviewing current knowledge concerning epigenetic molecular mechanisms, as well as recent results suggesting disruption of plasticity and memory formation during aging. Finally, several open questions will be discussed that we believe will fuel experimental discovery.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of epigenetic mechanisms. (A) In the nucleus, DNA coils and condenses around histones. Each octameric histone core contains two copies each of histones H2A, H2B, H3, and H4. The DNA–protein complex is referred to as chromatin. (B) The DNA-histone interaction occurs at the N-terminal tail of a histone, where for example on the H3 N-terminal tail, there are several sites for epigenetic marking via acetylation, methylation, and phosphorylation. (C) In and around gene promoters that are rich in cytosine-guanine nucleotides (CpG islands), methyl groups are transferred to CpG sites. This process, called DNA methylation, is catalyzed by a class of enzymes known at DNA methyltransferases.
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Figure 1: Schematic representation of epigenetic mechanisms. (A) In the nucleus, DNA coils and condenses around histones. Each octameric histone core contains two copies each of histones H2A, H2B, H3, and H4. The DNA–protein complex is referred to as chromatin. (B) The DNA-histone interaction occurs at the N-terminal tail of a histone, where for example on the H3 N-terminal tail, there are several sites for epigenetic marking via acetylation, methylation, and phosphorylation. (C) In and around gene promoters that are rich in cytosine-guanine nucleotides (CpG islands), methyl groups are transferred to CpG sites. This process, called DNA methylation, is catalyzed by a class of enzymes known at DNA methyltransferases.

Mentions: DNA methylation and histone modifications are two of the most extensively investigated epigenetic mechanisms (Figure 1). Until recently, it was thought that once laid down, these epigenetic marks remained unchanged for the lifetime of the organism, but recent studies in the nervous system have challenged this view. It is now apparent that epigenetic marks can be modified in response to an organism's experience, and play a key role in dynamically regulating the gene transcription supporting synaptic plasticity and long-term memory formation (Levenson and Sweatt, 2005; Graff and Mansuy, 2008; Jiang et al., 2008; Liu et al., 2009; Sweatt, 2009).


An epigenetic hypothesis of aging-related cognitive dysfunction.

Penner MR, Roth TL, Barnes CA, Sweatt JD - Front Aging Neurosci (2010)

Schematic representation of epigenetic mechanisms. (A) In the nucleus, DNA coils and condenses around histones. Each octameric histone core contains two copies each of histones H2A, H2B, H3, and H4. The DNA–protein complex is referred to as chromatin. (B) The DNA-histone interaction occurs at the N-terminal tail of a histone, where for example on the H3 N-terminal tail, there are several sites for epigenetic marking via acetylation, methylation, and phosphorylation. (C) In and around gene promoters that are rich in cytosine-guanine nucleotides (CpG islands), methyl groups are transferred to CpG sites. This process, called DNA methylation, is catalyzed by a class of enzymes known at DNA methyltransferases.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2874394&req=5

Figure 1: Schematic representation of epigenetic mechanisms. (A) In the nucleus, DNA coils and condenses around histones. Each octameric histone core contains two copies each of histones H2A, H2B, H3, and H4. The DNA–protein complex is referred to as chromatin. (B) The DNA-histone interaction occurs at the N-terminal tail of a histone, where for example on the H3 N-terminal tail, there are several sites for epigenetic marking via acetylation, methylation, and phosphorylation. (C) In and around gene promoters that are rich in cytosine-guanine nucleotides (CpG islands), methyl groups are transferred to CpG sites. This process, called DNA methylation, is catalyzed by a class of enzymes known at DNA methyltransferases.
Mentions: DNA methylation and histone modifications are two of the most extensively investigated epigenetic mechanisms (Figure 1). Until recently, it was thought that once laid down, these epigenetic marks remained unchanged for the lifetime of the organism, but recent studies in the nervous system have challenged this view. It is now apparent that epigenetic marks can be modified in response to an organism's experience, and play a key role in dynamically regulating the gene transcription supporting synaptic plasticity and long-term memory formation (Levenson and Sweatt, 2005; Graff and Mansuy, 2008; Jiang et al., 2008; Liu et al., 2009; Sweatt, 2009).

Bottom Line: These mechanisms, in turn, result in alterations in specific patterns of gene expression.Here we focus on this theme, reviewing current knowledge concerning epigenetic molecular mechanisms, as well as recent results suggesting disruption of plasticity and memory formation during aging.Finally, several open questions will be discussed that we believe will fuel experimental discovery.

View Article: PubMed Central - PubMed

Affiliation: Arizona Research Laboratories Division of Neural Systems, Memory and Aging and Evelyn F. McKnight Brain Institute, University of Arizona Tucson, AZ, USA.

ABSTRACT
This brief review will focus on a new hypothesis for the role of epigenetic mechanisms in aging-related disruptions of synaptic plasticity and memory. Epigenetics refers to a set of potentially self-perpetuating, covalent modifications of DNA and post-translational modifications of nuclear proteins that produce lasting alterations in chromatin structure. These mechanisms, in turn, result in alterations in specific patterns of gene expression. Aging-related memory decline is manifest prominently in declarative/episodic memory and working memory, memory modalities anatomically based largely in the hippocampus and prefrontal cortex, respectively. The neurobiological underpinnings of age-related memory deficits include aberrant changes in gene transcription that ultimately affect the ability of the aged brain to be "plastic". The molecular mechanisms underlying these changes in gene transcription are not currently known, but recent work points toward a potential novel mechanism, dysregulation of epigenetic mechanisms. This has led us to hypothesize that dysregulation of epigenetic control mechanisms and aberrant epigenetic "marks" drive aging-related cognitive dysfunction. Here we focus on this theme, reviewing current knowledge concerning epigenetic molecular mechanisms, as well as recent results suggesting disruption of plasticity and memory formation during aging. Finally, several open questions will be discussed that we believe will fuel experimental discovery.

No MeSH data available.


Related in: MedlinePlus