Histone Acetylation: Epigenetic Achilles’ Heel of Memory in Aging

Several recent studies have shown that memory formation, learning, and age-associated cognitive decline are linked to remodeling of chromatin proteins (see ARF related news story on Fischer et al., 2007; ARF related news story on Guan et al., 2009; and Gupta et al., 2010). Chromatin is the coiled histone protein and DNA structure that packs our chromosomes into our cells. Modifications of histone proteins, such as methylation and acetylation, can affect how tightly packed—and therefore how accessible for expression—the genes in our DNA are.

In tomorrow’s Science, researchers led by André Fischer at the Laboratory for Aging and Cognitive Diseases in the European Neuroscience Institute in Göttingen, Germany, demonstrate that alterations in learning-dependent acetylation at a specific histone site may be an early biomarker of memory impairment during aging. The group also shows that restoring histone acetylation can restore memory consolidation and learning-induced changes in gene expression that are ordinarily altered in aging brains.

“The world's scientific community may be one step closer to understanding age-related memory loss and to developing a drug that might help boost memory,” remarked David Sweatt from the University of Birmingham at Alabama in an e-mail comment to ARF about this study. Sweatt published an accompanying Perspectives article in the same issue of Science.

In their experiments, first authors Shahaf Peleg, Farahnaz Sananbenesi, and Athanasios Zovoilis used a contextual fear conditioning task to measure associative hippocampal learning in young (three-month-old), adult (eight-month-old), and middle-aged (16-month-old) mice. Mice in all age groups learned to associate a new environment with a mild foot shock. However, middle-aged mice showed less freezing behavior during a memory test, indicating that their associative memory was slightly impaired. Researchers also saw similar impairments in a Morris water maze test for spatial memory.

When Fischer and colleagues analyzed hippocampal gene expression of young mice after the fear conditioning task, they saw altered expression of more than 1,500 genes linked to associative learning. In contrast, they saw almost no change in the gene expression of middle-aged mice after learning. Middle-aged mice also failed to increase acetylation of histone H4 lysine 12 (H4K12) for those genes that were upregulated after learning in young mice. Increased acetylation is generally associated with both a more open chromatin structure and with increased gene expression.

Changes in acetylation at other histone sites and for genes that were downregulated or not regulated during learning were similar among age groups. Histone acetylation, hippocampal gene expression, and the activity of histone acetyltransferase and histone deacetylase (HDAC) enzymes were also similar between young and middle-aged mice that had not gone through the learning task. “Under basal conditions, there is no difference,” summarized Fischer in an interview with ARF. “But when [the mice] have to learn something and form a memory…the young mice are regulating 1,500 genes to go up transiently and then to go down. In the old mice, which are actually just a little bit impaired, none of this happens.”

Unlike most histone modifications, which tend to cluster in gene promoter regions, the scientists observed H4K12 acetylation mainly in gene coding regions. Fischer suggests that H4K12 acetylation is therefore less important to initiate transcription of these upregulated genes than it is to elongate transcription.

Fischer likens the potential role of H4K12 in learning-associated gene expression to the process of starting and driving a car. All of the other machinery and components for gene expression are present, and transcription initiation (starting the car) can still occur properly. “But if you only have three wheels,” says Fischer, “you still cannot drive anywhere. The fourth wheel that is missing is this H4K12 [acetylation]. Everything else is fine, but the genome is not responding.”

Finally, the team showed that restoration of H4K12 acetylation using pharmacologic HDAC inhibitors can restore expression of learning-regulated genes and improve associative learning during fear conditioning. To test this, the authors injected suberoylanilide hydroxamic acid (SAHA) into the hippocampi of middle-aged mice one hour before they attempted the associative learning task. Mice treated with SAHA showed increased H4K12 acetylation in the coding regions of learning-associated genes, as well as higher expression of these genes. The authors saw similar results when they treated mice with the pan-HDAC inhibitor sodium butyrate, but not when they treated them with a different HDAC inhibitor that did not increase H4K12 acetylation.

These findings are consistent with previous studies that also showed better learning following treatment with HDAC inhibitors in mouse models of neurodegenerative disease, including two recent studies from the Sweatt and Arancio labs conducted in AD mouse models (see Kilgore et al., 2010; Francis et al., 2009; Sananbenesi and Fischer, 2009; and ARF related news story). Together, these results suggest that histone deacetylase inhibitors may improve cognitive function in both normal and disease-related memory decline.

Additional research is needed before these results can be extended to humans. Even so, Fischer is optimistic about the therapeutic potential of these findings. “I think there is now a clear focus on what needs to be targeted, and researchers just need to take it to the next step,” he says. “I think we aren’t far from a clinical application anymore.”—Elizabeth Eyler

Elizabeth Eyler is a freelance writer in Baltimore, Maryland.

Comments

    • User Profile Image Susan Su
      Massachusetts Institute of Technology
    • Posted:

    Age-related cognitive decline is considered to be a consequence of the normal aging process in healthy adults and can result in slight impairments in working memory and other functional tasks. However, in neurodegenerative disease states such as Alzheimer disease, dementia severely impairs one’s memory, intellectual and social abilities, and causes a loss of identity. While a full understanding of the cellular and molecular processes in age-related cognitive decline or dementia is still lacking, a growing body of evidence suggests that epigenetic regulation and dysfunction of specific genes may play a central role in the pathogenesis of neurological disorders (for review, see Roth and Sweatt, 2009).

    In the epigenetic landscape, various modifications, including histone acetylation or deacetylation, serve as important markers for chromatin remodeling and subsequently gene transcription. Histone deacetylase inhibitors (HDACi’s) allow for increased gene transcription by preventing the removal of the acetyl group on a lysine residue on a histone. HDACi’s have potential therapeutic applications for mouse models of Huntington disease (Hockly et al., 2003), Rubinstein-Taybi syndrome (Alarcon et al., 2004), and most recently, Alzheimer disease (Fischer et al., 2007; Guan et al., 2009).

    Now, for the first time, Fischer and colleagues have undertaken in this paper a comprehensive approach to screening epigenetic changes in normal aging mice. They examined various epigenetic modifications in different groups of mice and found only one residue, histone 4 lysine 12 (H4K12) acetylation, to be decreased in older mice. Moreover, these aged mice display impaired memory formation as measured by hippocampus-dependent contextual fear conditioning as well as spatial learning as shown by the Morris water maze tasks. These impairments were not due to alterations in neuronal morphology or differences in sensory components that would affect the task at hand.

    To further explore the underlying mechanisms for their observations, the authors performed an oligonucleotide microarray to determine if there are specific genes that are altered. They found no changes in HDAC activity; however, they noticed that there was a category of genes that they termed “learning-regulated genes” that are not properly regulated in older mice. Furthermore, ChIP-sequencing technology allowed the authors to probe which part of DNA exhibited altered H4K12 acetylation in aged mice. To this end, they found that the genomic region downstream of the transcription start site had impaired H4K12 acetylation and concluded that there is an impairment of transcriptional elongation. As proof of concept, the gene Formin 2 (Fmn2) is found to lack H4K12 acetylation in older mice. The Fmn2 knockout mice also display age-associated memory formation. Strikingly, this impairment was reversed after hippocampal SAHA (an HDACi) treatment, which, in turn, increased H4K12 acetylation, consistent with earlier observations.

    The paper compellingly demonstrates that a particular epigenetic marker, in this case H4K12 acetylation, is altered in age-related cognitive decline and leads to altered gene expression. Future studies will undoubtedly focus on the mechanisms that target H4K12 acetylation and the detection of other epigenetic changes that may be involved during the aging process. Nevertheless, this study is the first to address a key alteration in the epigenetic landscape that is specific to aging and occurs before any visible neuronal loss. It also highlights the intriguing concept of developing therapies that can potentially reverse dysregulated epigenetic markers during neurodegenerative states and restore memory.

    References:

    Roth TL, Sweatt JD. Regulation of chromatin structure in memory formation. Curr Opin Neurobiol. 2009 Jun;19(3):336-42. PubMed.

    Hockly E, Richon VM, Woodman B, Smith DL, Zhou X, Rosa E, Sathasivam K, Ghazi-Noori S, Mahal A, Lowden PA, Steffan JS, Marsh JL, Thompson LM, Lewis CM, Marks PA, Bates GP. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):2041-6. PubMed.

    Alarcón JM, Malleret G, Touzani K, Vronskaya S, Ishii S, Kandel ER, Barco A. Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron. 2004 Jun 24;42(6):947-59. PubMed.

    Fischer A, Sananbenesi F, Wang X, Dobbin M, Tsai LH. Recovery of learning and memory is associated with chromatin remodelling. Nature. 2007 May 10;447(7141):178-82. PubMed.

    Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, Nieland TJ, Zhou Y, Wang X, Mazitschek R, Bradner JE, DePinho RA, Jaenisch R, Tsai LH. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature. 2009 May 7;459(7243):55-60. PubMed.

    View all comments by Susan Su

  2. This article identifies altered histone acetylation as an early biomarker of memory impairment. More specifically, the authors show an altered acetylation response of a specific lysine residue, i.e., K12, of histone 4 in older mice, but not in young mice. Notably, age-dependent changes in K12 acetylation on H4 were ameliorated in mice treated with the drug SAHA, a pan-inhibitor of histone deacetylases. HDAC inhibitors may therefore provide a feasible approach for treating memory loss in human neurodegenerative conditions like Alzheimer disease. In that respect, future studies will have to demonstrate memory improvement in Alzheimer disease animal models treated with HDAC inhibitors, and correlate efficacy with changes in the acetylation state of H4K12. If these studies are positive, developing HDAC-based therapeutics appears feasible for symptomatic treatment of AD. However, while these results provide optimism, I would recommend caution at this stage, because results achieved in early pre-clinical studies often do not translate into efficacious effects in human trials.

    View all comments by Aleksey Kazantsev

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References

News Citations

  1. Memories—Forgotten, But Not Gone?
  2. It’s an HDAC2 Wrap— Memory-suppressing DNA Modifier Identified
  3. For Better Memory, Try Keeping Your HAT On…

Paper Citations

  1. Fischer A, Sananbenesi F, Wang X, Dobbin M, Tsai LH. Recovery of learning and memory is associated with chromatin remodelling. Nature. 2007 May 10;447(7141):178-82. PubMed.
  2. Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, Nieland TJ, Zhou Y, Wang X, Mazitschek R, Bradner JE, DePinho RA, Jaenisch R, Tsai LH. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature. 2009 May 7;459(7243):55-60. PubMed.
  3. Gupta S, Kim SY, Artis S, Molfese DL, Schumacher A, Sweatt JD, Paylor RE, Lubin FD. Histone methylation regulates memory formation. J Neurosci. 2010 Mar 10;30(10):3589-99. PubMed.
  4. Kilgore M, Miller CA, Fass DM, Hennig KM, Haggarty SJ, Sweatt JD, Rumbaugh G. Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer's disease. Neuropsychopharmacology. 2010 Mar;35(4):870-80. PubMed.
  5. Francis YI, Fà M, Ashraf H, Zhang H, Staniszewski A, Latchman DS, Arancio O. Dysregulation of histone acetylation in the APP/PS1 mouse model of Alzheimer's disease. J Alzheimers Dis. 2009;18(1):131-9. PubMed.
  6. Sananbenesi F, Fischer A. The epigenetic bottleneck of neurodegenerative and psychiatric diseases. Biol Chem. 2009 Nov;390(11):1145-53. PubMed.

Further Reading

Primary Papers

  1. Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S, Agis-Balboa RC, Cota P, Wittnam JL, Gogol-Doering A, Opitz L, Salinas-Riester G, Dettenhofer M, Kang H, Farinelli L, Chen W, Fischer A. Altered histone acetylation is associated with age-dependent memory impairment in mice. Science. 2010 May 7;328(5979):753-6. PubMed.
  2. Sweatt JD. Neuroscience. Epigenetics and cognitive aging. Science. 2010 May 7;328(5979):701-2. PubMed.

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