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15 March 2010. Shhh! Is silence conducive to learning and memory? Perhaps. But before you pack for the Buddhist temple, we’re talking gene silencing here, and only certain genes. In the March 10 Journal of Neuroscience, researchers report that long-term memory requires methylation of histones, core components of the chromatin spools that wind DNA. According to the research, learning causes histone methylation that prevents DNA from unwinding, thereby silencing genes. But that’s not the full story. Some methylation patterns actually do the opposite, weakening chromatin and activating genes. The work suggests a complex balance between gene silencing and activation in the formation of memories, and the researchers identify some genes that may be involved. These include those for brain-derived neurotrophic factor (BDNF) and Zif268, both known players in memory formation (see ARF related news story).
Transcriptional regulation is part and parcel of long-term memory consolidation. Traditionally, this regulation was seen as the domain of transcription factors such as CREB (see ARF related news story). But beyond that, post-translational modification of histones dramatically alters the strength of the chromatin, either exposing DNA or shielding it from factors such as CREB. Links between long-term memory and acetylation and phosphorylation of these proteins emerged (see, e.g., ARF related news story and Chwang et al., 2006), but whether their methylation is also involved has not been clear.
Led by senior author Farah Lubin at the University of Alabama, Birmingham, first author Swati Gupta and colleagues correlated contextual fear conditioning with histone methylation patterns in the hippocampus of young male rats. In this learning paradigm, animals are trained to associate exposure to a new environment with a mild foot shock. The training caused two different methylation events. First, simply placing the animal in a new environment led, one hour later, to demethylation of histone H3 on amino acid lysine nine, dubbed, in short H3K9. The full contextual fear paradigm had the same effect, but in addition, the researchers found trimethylation of H3K4. This additional methylation event did not occur if the new environment and the foot shock were separated by two hours, indicating that it was not simply the result of stress from the foot shock. Interestingly, methylation of H3K9 is normally associated with transcriptional repression, whereas H3K4 methylation activates genes. Since the latter only emerged after the full contextual fear conditioning paradigm, the result implies “that the H3K4 mark may be an associative-learning-specific signal,” write the authors.
This set of experiments demonstrated a relationship between learning and methylation, but did not prove that the latter was a prerequisite for the former. To investigate that, Gupta and colleagues turned to an Mll methylase mutant mouse, since there is evidence this enzyme specifically modifies H3K4 (see Milne et al., 2002). The researchers found that Mll+/- heterozygotes were slow to catch on in the associative learning task. Twenty-four hours after training, methylase-deficient animals only froze one in five times when re-exposed to the fear context, whereas normal littermates froze four in five times. Curiously, the researchers did not directly measure H3K4 trimethylation in the Mll heterozygotes.
If both silencing and activation of genes through histone methylation is important for hippocampal-dependent learning and memory, then are specific sites of histone methylation especially important? In an attempt to address this question, the authors chose to examine methylation patterns around the promoters of BDNF and Zif268, two genes known to be involved in memory consolidation (see ARF related news story). When Gupta and colleagues isolated those regions by chromatin immunoprecipitation, they found increased H3K4 methylation at both the Zif268 and BDNF promoter 1 regions following contextual fear training but not context training alone. “Together, these results demonstrate active regulation of H3K4 trimethylation within specific gene promoters, and further demonstrate that H3K4 trimethylation is regulated in response to fear conditioning,” write the authors.
This research may open up a new avenue for studying memory formation, perhaps even a ”rotary” that connects several others as well. Histone acetylation and DNA methylation also play roles in learning and memory, and histone methylation can influence both. Methylation at H3K9, for example, competes with acetylation at the same site. In agreement with this, the authors found that the general histone deacetylase (HDAC) inhibitor, sodium butyrate, blocks H3K9 methylation induced by fear conditioning. Histone methylation can alter DNA methylation, which itself can alter gene expression. For example, work from Huda Zoghbi’s group at Baylor College of Medicine, Houston, Texas, showed that CREB can recruit the methyl-DNA binding protein MeCP2 to promoters to activate transcription (see Chahrour et al., 2008). Originally, the Rett syndrome gene MeCP2 was fingered as a transcriptional repressor. Interestingly, Gupta and colleagues present evidence that MeCP2 binding is also increased on the Zif268 promoter in response to histone methylation during contextual fear learning.
Histone acetylation is a hot area of memory research, given that HDAC inhibitors enhance learning and memory (see ARF related news story). There is also some evidence that histone methylation is changed in some cases of schizophrenia (see Akbarian and Huang, 2009). Whether histone methylation turns out to be relevant to memory disorders such as Alzheimer’s remains to be seen.—Tom Fagan.
Reference:
Gupta W, Kim SY, Artis S, Molfese DL, Schumacher A, Sweatt JD, Paylor RE, Lubin FD. Histone methylation regulates memory formation. Journal of Neuroscience 2010, March 10; 30:3589-3599. Abstract
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Comments on News and Primary Papers |
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Primary Papers: Histone methylation regulates memory formation.
Comment by: Roberta Diaz Brinton, ARF Advisor
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Submitted 21 March 2010
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Posted 23 March 2010
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 I recommend this paper
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Comments on Related News |
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Related News: For Better Memory, Try Keeping Your HAT On…
Comment by: George M. Martin, ARF Advisor (Disclosure)
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Submitted 29 June 2004
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Posted 29 June 2004
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Tom Fagan has done a very nice job of calling our attention to these exceptionally important and concordant sets of results supporting Robin Holliday's original proposal for a role for epigenetic modifications in long- term memory ( Holliday, 1999). Robin emphasized methylations and demethylations of CpGs in his 1999 paper; less was known at that time about alterations in gene expression associated with chromatin modifications by histone acetylases and deacetylases.
The important phenotypic consequences of haploinsufficiency for the CREB binding protein provides a rationale for an investigation of potential roles of genetic polymorphisms, or better, of haplotype variations, in the modulation of long-term memory in human subjects.
PS: I also want to give special thanks to Tom Fagan for having highlighted the excellent accompanying commentary by Kelsey C. Martin and YE Sun. (Kelsey Martin is my daughter!)
 View all comments by George M. Martin |
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Related News: For Better Memory, Try Keeping Your HAT On…
Comment by: Mary Reid
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Submitted 30 June 2004
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Posted 1 July 2004
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I see that many of the signs of Rubenstein-Taybi syndrome are also reported in Down's syndrome.
The study by Branchi et al. (1) finding that overexpression of DYRK1A results in increased phosphorylation of FKHR, high levels of cyclin B1 and increased phosphorylation of CREB is of great interest.
They report increased brain weight associated with DYRK1A overexpression, yet reduced brain weight is reported in Down's syndrome.
Of further interest is the study by Daitoku et al. (2) finding that CREB-binding protein binds and acetylates FKHR and that Sir2 binds and deacetylates residues acetylated by CREB-binding protein.
Do the CBP mutations reported in RTS allow for FKHR binding?
Ironic that the CREB pathway required for learning and memory is also affected by the longevity gene, Sir2.
Is this one reason for the mental retardation and reduced lifespan reported in Down's syndrome?
References:
(1)
Journal of Neuropathology and Experimental Neurology: Vol. 63, No. 5, pp. 429–440.
Transgenic...
Read more
I see that many of the signs of Rubenstein-Taybi syndrome are also reported in Down's syndrome.
The study by Branchi et al. (1) finding that overexpression of DYRK1A results in increased phosphorylation of FKHR, high levels of cyclin B1 and increased phosphorylation of CREB is of great interest.
They report increased brain weight associated with DYRK1A overexpression, yet reduced brain weight is reported in Down's syndrome.
Of further interest is the study by Daitoku et al. (2) finding that CREB-binding protein binds and acetylates FKHR and that Sir2 binds and deacetylates residues acetylated by CREB-binding protein.
Do the CBP mutations reported in RTS allow for FKHR binding?
Ironic that the CREB pathway required for learning and memory is also affected by the longevity gene, Sir2.
Is this one reason for the mental retardation and reduced lifespan reported in Down's syndrome?
References:
(1)
Journal of Neuropathology and Experimental Neurology: Vol. 63, No. 5, pp. 429–440.
Transgenic Mouse In Vivo Library of Human Down Syndrome Critical Abstract
(2) Proc Natl Acad Sci U S A. 2004 Jun 25 [Epub ahead of print]
Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity.
Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, Miyagishi M, Nakajima T, Fukamizu A. Abstract
View all comments by Mary Reid |
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Related News: For Better Memory, Try Keeping Your HAT On…
Comment by: Mary Reid
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Submitted 2 July 2004
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Posted 5 July 2004
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Which of the human sirtuins might target FKHR? Might we suspect SIRT2, as North et al. (1) find that it is a tubulin deacetylase.
Hempen et al. (2) report decreased acetylated alpha-tubulin in neurofibrillary tangle-bearing neurons in AD.
Does the overexpression of DYRK1A reported by Funakoshi et al. (3), which has resulted in chromosome missegregation, suggest that it may be a downstream effect on FKHR/SIRT2 and resultant deacetylated alpha-tubulin?
Might we suspect a SIRT1/FKHR association? Takata and Ishikawa (4) report that SIRT1 associates with HES1 and HEY2.
Does the fact that DYRK1A overexpression resulting in increased phosphorylated CREB also implicate this gene product in the increased presenilin-1 levels found in Down's syndrome?
Mitsuda et al. (5) report that CREB controls expression of presenilin-1.
I see that the Sambamurti group (6) find a CREB binding site on BACE.
References:
(1) North BJ, Marshall BL, Borra MT, Denu JM, Verdin E. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell. 2003...
Read more
Which of the human sirtuins might target FKHR? Might we suspect SIRT2, as North et al. (1) find that it is a tubulin deacetylase.
Hempen et al. (2) report decreased acetylated alpha-tubulin in neurofibrillary tangle-bearing neurons in AD.
Does the overexpression of DYRK1A reported by Funakoshi et al. (3), which has resulted in chromosome missegregation, suggest that it may be a downstream effect on FKHR/SIRT2 and resultant deacetylated alpha-tubulin?
Might we suspect a SIRT1/FKHR association? Takata and Ishikawa (4) report that SIRT1 associates with HES1 and HEY2.
Does the fact that DYRK1A overexpression resulting in increased phosphorylated CREB also implicate this gene product in the increased presenilin-1 levels found in Down's syndrome?
Mitsuda et al. (5) report that CREB controls expression of presenilin-1.
I see that the Sambamurti group (6) find a CREB binding site on BACE.
References:
(1) North BJ, Marshall BL, Borra MT, Denu JM, Verdin E. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell. 2003 Feb;11(2):437-44. Abstract
(2) J Neuropathol Exp Neurol. 1996 Sep;55(9):964-72.
Reduction of acetylated alpha-tubulin immunoreactivity in neurofibrillary tangle-bearing neurons in Alzheimer's disease.
Hempen B, Brion JP. Abstract
(3) BMC Cell Biol. 2003 Sep 10;4(1):12. Overexpression of the human MNB/DYRK1A gene induces formation of multinucleate cells through overduplication of the centrosome. Funakoshi E, Hori T, Haraguchi T, Hiraoka Y, Kudoh J, Shimizu N, Ito F. Abstract
(4) Biochem Biophys Res Commun. 2003 Jan 31;301(1):250-7.
Human Sir2-related protein SIRT1 associates with the bHLH repressors HES1 and HEY2 and is involved in HES1- and HEY2-mediated transcriptional repression.
Takata T, Ishikawa F. Abstract
(5) J Biol Chem. 2001 Mar 30;276(13):9688-98. Epub 2000 Dec 14. Activated cAMP-response element-binding protein regulates neuronal expression of presenilin-1. Mitsuda N, Ohkubo N, Tamatani M, Lee YD, Taniguchi M, Namikawa K, Kiyama H, Yamaguchi A, Sato N, Sakata K, Ogihara T, Vitek MP, Tohyama M. Abstract
(6) FASEB J. 2004 Jun;18(9):1034-6. Epub 2004 Apr 01. Gene structure and organization of the human beta-secretase (BACE) promoter. Sambamurti K, Kinsey R, Maloney B, Ge YW, Lahiri DK. Abstract
View all comments by Mary Reid |
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Related News: DC: Developing But Debatable—Deacetylase Inhibitors for CNS Disease?
Comment by: Sigfrido Scarpa
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Submitted 15 December 2008
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Posted 16 December 2008
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Deacetylation is a wide and complex epigenetic mechanism, which could involve undesired targets. The use of specific compounds to obtain epigenetic silencing of genes in AD treatment is much more preferable and safe. We published several papers in which we show the involvement of gene methylation in AD pathology. References: Fuso A, Nicolia V, Cavallaro RA, Ricceri L, D'Anselmi F, Coluccia P, Calamandrei G, Scarpa S. B-vitamin deprivation induces hyperhomocysteinemia and brain S-adenosylhomocysteine, depletes brain S-adenosylmethionine, and enhances PS1 and BACE expression and amyloid-beta deposition in mice. Mol Cell Neurosci. 2008 Apr;37(4):731-46. Abstract
Cavallaro RA, Fuso A, D'Anselmi F, Seminara L, Scarpa S. The effect of S-adenosylmethionine on CNS gene expression studied by cDNA microarray analysis. J Alzheimers Dis. 2006 Aug;9(4):415-9. Abstract
View all comments by Sigfrido Scarpa |
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