The role of histones

From a structural perspective, histones can be considered to consist of a tri-partite organization in which a central histone fold domain [81] is flanked by N- and C-terminal regions tails with a low level of folding. The histone fold is responsible for the histone bundle and handshake interactions that hold the histone octamer together [45,265,307,308] while the tails do not appear to have any major role in the stability of the octamer subunits [309]. 

From all the above it would be expected that only histone variability (variants or post-translational modification) affecting the histone fold or C-terminal domains would have a major effect on nucleosome stability in agreement with the experimental results that will be described in the following sections. 

A good example of the effects of histone variability on nucleosome stability is provided by the yeast histones, which are very divergent from their vertebrate counterparts [312]. Physical [313], biochemical [314], and crystallographic [315] analyses have produced evidence for a lower nucleosome stability resulting from the association of these histones with DNA. The lower stability conferred by yeast histones to the nucleosome when compared to vertebrate histones is in line with the more dynamic metabolic demand of this organism as most of its genome exists as euchromatin [316]. 

Of the three major structural components that can affect chromatin folding linker DNA length, histone tails and linker histones, the last two are critical for the dynamic aspects of the process and hence it would be expected that 

Experimental results regarding the role of the histone tails indicate that these histone domains play a critical role in chromatin folding [358,365]. Removal as well as the modification (acetylation) of the lysine amino acids within these regions produces an imbalance of the electrostatic interactions, which results in a hierarchically impaired folding ability (H3/H4-H2A/H2B H3/H4 H2A/H2B) of the chromatin fiber [358,366-369]. Therefore, sources of histone tail variability (histone variants and post-translational modifications other than lysine acetylation) are also likely to alter the extent of folding of chromatin. 

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NCP crystals. There were two facets to this approach. First, it was necessary to reconstitute NCPs from a defined sequence DNA that phased precisely on the histone core to circumvent the random sequence disorder. It was obvious that the DNA was important for the quality of the diffraction from NCP crystals but the role of histone heterogeneity was not so clear. Heavy atom derivatives (i.e., electron rich elements bound in specific positions on the proteins) were not readily prepared by standard soaking experiments, due to a paucity of binding sites. Hence, it was necessary to selectively mutate amino acid residues in the histones to create binding sites for heavy atoms. 

Tordera, V., Sendra, R., and Perez-Ortin, J.E. (1993) The role of histones and their modifications in the informative content of chromatin. Experientia 49, 780-788. 

The role of histone becomes, thus, part of the problem of how the environment affects gene activity. Biology has by now outgrown the abstract and rigid limitations of classical genetics for now it is dear that the chromosome, like other centres of vital activity, is subject to regulation by feed-back of the periphery. A. E. Mirsky, 1965 (sic ) [1]... 

Some 40 years later we basically stand in awe when reading those matter-of-facdy spoken but definitely at that time prophetic words from Dr. Mirsky. Already in 1950 Stedman had discussed the role of histones in differentiation [2] and in 1964 Allfrey reported on the acetylation of histones [3]. The words of Mirsky are the concluding remarks of a Ciba Foundation symposium on histones and their role in transfer of genetic information. There it was discussed that chromatin represents a. .. metabolically active region of the nucleus (p. 48). Many fine bands had been resolved in electrophoretic analysis of the histones but of course many details of the processes involved totally eluded the scientific knowledge of these days. But already then, a functional correlation between histone acetylation and the RNA-synthetic capacity of the chromatin was suggested. 

Yoshida, M., Horinouchi, S., and Beppu, T. (1995) Trichostatin A and trapoxin Novel chemical probes for the role of histone acetylation in chromatin structure and function. Bioessays 17, 423-430. 

The research conducted in the author s laboratory was supported by a grant from the NIH (HD 22681). The author would also like to thank Mel DePamphilis and Bryan Turner for many stimulating discussions regarding regulation of transcription in mouse embryos and the role of histone acetylation in regulating gene expression. 

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