This is the classic paper where the histone code hypothesis was proposed. Evidences that support this were that (1) histone modifications (acetylation, phosphorylation, methylation) may alter chromatin structure, influencing gene expression; and (2) growing data showing diversity and biological specificity associated with different histone modification patterns. Characterization of histone acetyl- transferases (HATs) and deacetylases (HDACs) provided further support, because they brought the possibility of steady- state regulation of the process. On the other hand, structural periodicities between modified residues may suggest that combinations of modified amino acids could have different meanings (e.g. a code)
Considering only electrostatic requirements for folding the chromatin polymer, histone acetylation [...] and histone phosphorylation [...] would cause decondensation of the chromatin fibre. Thus, the use of multiple marks on histone tails [...] could serve to amplify the readout of upstream signalling pathways causing greater changes in the overall charge density of tails that lead to greater changes in the chromatin structure of target genes. [...] If the function of H3 phosphorylation is to 'open' chromatin, how then can H3 phosphorylation at the same site also be involved in chromatin condensation? [...] Perhaps a single histone modification does not function alone. We will refer to the hypothesis -that multiple histone modifications, acting in a combinatorial or sequential fashion on one or multiple histone tails, specify unique downstream functions- as the histone code hypothesis.
How is this code established? Authors proposed that modifications are located close enough to influence the ability of the modifying enzymes to add more covalent groups, and these modifications might in turn influence the outcome on other histone tails that are in contact. How is this code read? Relaxation of the chromatin could promote the binding of efectors, or alternatively, histone modifications could act as receptors that recruit distinct specific sets of proteins. For example, PCAF binds acetylated lysine in H3 or H4 -which might suggest the possibility of specific binding motifs recognizing histone modifications. Authors pointed that all these evidences remark the necessity for identifying:
- the complete dictionary of histone modifications;
- phenotypes associated with each modification;
- modifying enzymes and their recruitment processes; and
- the way that these modifications specify all these interactions.
Perhaps the most difficult questions are those that were not discussed in the paper: How is this code passed through generations? How this code appeared and evolved, since some histone modifications seemed to be species- specific?
Strahl DB. and Allis CD. 2000. Nature 403:41-45
epigenetics
