Biology of Histone Modifications

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The components of chromatin, i.e. DNA, and the histone proteins that organise it into nucleosomes, which enable the compaction of DNA into higher-order chromatin structures. 

In some cases, general roles for these covalent post-translational modifications have been identified, e.g. hyperacetylation of histones correlates with 

Here we review current knowledge on the enzymes and related binding proteins that are involved in covalent modifications to histones. We begin with a brief overview of the field aimed at the non-expert, then focus on the covalent modifications themselves as catalysed by specific enzymes. We also focus on the consequences of these modifications for binding interactions with other proteins that modulate gene expression. The field is one that is rapidly evolving and we hope to convey some of the excitement that we feel about recent discoveries in histone science, particularly from a molecular perspective. Two inhibitors of histone modifying enzymes are in clinical use, with more likely to be introduced in the near future. Thus, the development of modifiers of histone biochemistry is of medicinal as well as basic interest. 

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Chemical Biology of Histone Modifications Table 5.2 Human histone deacetylases. 

Latham, J.A. and Dent, S.Y. (2007) Cross-regulation of histone modifications. Nature Structural S, Molecular Biology, 14, 1017-1024. 

The biologic processes described above and cytosine methylation, fit the epigenetic definition well because they are heritable. However, whether the entire repertoire of histone modifications is heritable remains to be established. In fact, it is likely that only a subset will have epigenetic inheritance. 

These studies demonstrate that H2A (T119) phosphorylation by NHK-1 regulates mitotic and meiotic progression. However, it remains unclear what is the biological function of other histone H2A posphorylation sites and how they impact the many other histone modifications. 

We have discussed phosphorylation of histone H3, which has been studied in many organisms. Phosphorylation of histone H3 (SIO) has two opposite main functions. One is necessary to initiate chromosome condensation during mitosis and meiosis, while the other is transcriptional activation. Current evidence shows that a combination of phosphorylation of H3 (SIO) and methylation of H3 (K9) or acetylation H3 (K9, K14) play important roles in these phenomena including cell cycle related chromosome dynamics and transcriptional activation. These results suggest that a combination of different histone modifications excute different biological outcomes. 

Acetylation is a reversible modification on proteins that can also contribute to protein localization and function. Acetylation of lysine residues in histone proteins can control the secondary structure of chromatin as well as gene expression levels from certain loci, and chromatin remodeling and its consequences in a variety of molecular and cell biological questions are intensely researched. Many other proteins undergo reversible acetylation, and the functional consequences of these modifications are poorly understood in many cases. 

Bhaumik, S.R., Smilh, E. and Shilatifard, A. (2007) Covalent modifications of histones during development and disease pathogenesis. Nature Structural ei Molecular Biology, 14, 1008—1016. 

The use of different approaches to study complex histone modification patterns ranging from the bottom up approach that allows a detailed and quantitative measurement of particular histone modifications to the top down methods that help the dissection of interdependencies between different modifications will greatly facilitate the analysis of complex modification patterns and provide a deeper insight into the biological role of these patterns. 

Shogren-Knaak, M.A., Fry, C.J. and Peterson, C.L. (2003) A native peptide ligation strategy for deciphering nudeosomal histone modifications. The Journal of Biological Chemistry, 278, 15744-15748. 

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