Epigenetics, Histone Proteins, and Alzheimer’s Disease

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Epigenetic effects were first described by Conrad Waddington in 1942 as phenotypic changes resulting from an organism interacting with its environment.1 Today, epigenetics is an emerging field of interest in the biological world describing heritable effects in gene expression that are not based on the genetic sequence. One known epigenetic mechanism includes posttranslational modifications of histone proteins.

Histone proteins are found in the nuclei of nearly all eukaryotes and function to package DNA into nucleosomes. Histone proteins can be heavily decorated with posttranslational modifications (PTMs), such as acetyl-, methyl-, and phosphoryl- groups at distinct amino acid residues. These modifications are mainly located in the N-terminal tails of the histone and protrude from the core nucleosome structure. Gene regulation, and the downstream epigenetic effects, can also depend on the cis or trans orientation of the PTMs.2

One PTM, acetylation, is an important determinant of cell replication, differentiation, and death.3 Zhang, et al. investigated the acetylation of histone proteins in Alzheimer’s disease (AD) pathology found in postmortem human brain tissue compared to neurological controls. To study histone acetylation, histones were isolated from frozen temporal lobe samples of patients with advanced AD. Histones were quantified using Selected-reaction-monitoring (SRM)-based targeted proteomics, a technique previously described as a LC-MS/MS-based technique and previously demonstrated by the Zhang lab.4 Histones were also analyzed using western blot analysis and LC-MS/MS-TMT (tandem-mass-tagging) quantitative proteomics. The results of these three experimental strategies were in agreement, which further validated the specificity and sensitivity of the targeted proteomics methods. Histone acetylation was significantly reduced throughout in the AD temporal lobe compared to matched controls. In particular, the histone H3 K18/K23 acetylation was significantly reduced.

Alzheimer’s disease and aging have also been associated with loss of histone acetylation in mouse model studies.5 In addition, Francis et al. found cognitively impaired mice had a 50% reduced H4 acetylation in APP/PS1 mice than wild-type littermates.6 In mice, histone deacetylase inhibitors have also been shown to restore histone acetylation and improve memory in mice with age-related impairments or in models for other neurodegenerative diseases.7

Further studies of histone acetylation in AD could lead to target therapies in the disease pathology of neurodegenerative diseases, as well as an increased understanding of how epigenetic mechanisms, such as histone acetylation, alter gene regulation.

References

1. Waddington, C.H., (1942). ‘The epigenotype‘, Endeavour, 1942 (1), (pp. 18-20)

2. Sidoli, S., Cheng, L., and Jensen O.N. (2012) ‘Proteomics in chromatin biology and epigenetics: Elucidation of post-translational modifications of histone proteins by mass spectrometry‘, Journal of Proteomics, 75 (12), (pp. 3419-3433)

3. Zhang. K., et al. (2012) ‘Targeted proteomics for quantification of histone acetylation in Alzheimer’s disease‘, Proteomics, 12 (8), (pp. 1261-1268)

4. Darwanto, A., et al., (2010) ‘A modified “cross-talk” between histone H2B Lys-120 ubiquitination and H3 Lys-K79 methylation‘, The Journal of Biological Chemistry, 285 (28), (pp. 21868-21876)

5. Govindarajan, N., et al. (2011) ‘Sodium butyrate improves memory function in an Alzheimer’s disease model when administered at an advanced stage of disease progression‘, Journal of Alzheimer’s Disease, 26 (1), (pp.187-197)

6. Francis, Y.I., et al., (2009) ‘Dysregulation of histone acetylation in the APP/PS1 mouse model of Alzheimer’s disease‘, Journal of Alzheimer’s Disease, 18 (1), (pp. 131-139)

7. Kilgore, M., et al., (2010) ‘Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer’s disease‘, Neuropsychopharmacology, 35 (4), (pp. 870-880)

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