Subject histones

Abstract Histone proteins that form the nucleosome core are subject to a variety of post-translational... 

In this connection, it must also be borne in mind that the deoxyribonucleic acids subjected to analysis have probably not been homogeneous. Deoxyribonucleic acids have been fractionated by making use of their different solubilities in normal saline,186 by extracting thymus nucleo-his-tone with sodium chloride solutions of increasing concentration,187 by ion-exchange,187 and also by adsorption of the polynucleotide onto histone immobilized on a kieselguhr support.123 It is possible, however, that these are artefacts, since it has been shown that deoxyribonucleic acid fractions extracted from calf-thymus nucleohistone may or may not vary in composition according to the previous treatment of the material.188... 

Since their discovery in 1884 by Kossel, the histones have been the subject of comprehensive study. This work has been summarized in several books and reviews (Phillips, 1971 DeLange and Smith, 1971, 1972 Hnilica, 1972 Elgin and Weintraub, 1975 Li, 1977 Isenberg, 1978, 1979 Von Holt et al., 1979). Therefore, no attempt will be made here to give a comprehensive treatment of the work already reviewed. However, a brief discussion of some special properties of the histones will be presented before we proceed to the treatment of those structural aspects of the histones which are the focus of this article. 

The phosphorylation of histone HI has been reviewed several times in recent years (Dixon et al., 1975 Elgin and Weintraub, 1975 Gurley et al., 1978 Langan, 1978 Isenberg, 1978). Therefore, we will not give a full discussion of the subject here. Only points relevant to HI-DNA interaction will be mentioned. 

The topic of histone acetylation has been the subject of extensive reviews (Dixon et al., 1975 Dixon, 1976 Allfrey, 1977 Isenberg, 1979). Acetylation occurs at specific lysine residues. In the case of the four core histones the acetylation sites are all located in the amino-terminal half of the molecule. 

A true appreciation of the subtle and complex ways in which the nucleosome can influence gene expression, has come only recently, largely through studies of the post-translational modifications to which all histones are subject and of the enzymes that add and remove these modifications. It has been known for many years that the histone N-terminal tails are exposed on the surface of the nucleosome and that selected amino acid residues are subject to a variety of enzyme-catalyzed, post-translational modifications. These include acetylation of lysines, phosphorylation of serines, and methylation of lysines and arginines ([6,7], see also chapters by Davie, and Ausio and Abbott, this volume). The locations of the histone N-terminal tails in the nucleosome and the residues that can be modified are shown in Fig. 1. 

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]... 

In cells of the mammary gland, either in normal epithelial or in cancerous cells, the packaging of chromosomal DNA into chromatin restricts the access of the transcription machinery, thereby causing transcriptional repression. The basic N-termini of histones are subject to post-translational modifications, including lysine acetylation, lysine and arginine methylation, serine phosphorylation and ubiquitinylation [56]. It has been proposed in the histone code hypothesis that the intricate pattern of modifications of the N-terminal histone tail influences gene regulation [57]. 

While bound to its cognate response element, the liganded/dimerized receptor recruits co-activator proteins that link with additional transcription factors, often leading to acetylation of histones, which opens up the nucleo-some to admit RNA polymerase II to the transcription start site. As would be expected, given that there is a sizeable superfamily of nuclear receptors and numerous interacting proteins, this simplified central theme is subject to many variations and complexities that allow subtle fine-tuning of regulatory responses. 

The functionality of some chromatin modification patterns is well established however, the vast majority remains poorly understood. Given that histones are subject to more than 100 post-translational modihcations, considerable efforts to characterize the mammalian epigenome are ongoing. 

Thermostabilization of double-stranded DNA is provided by base pairing (1) and base stacking (see Reference 27 and references therein) complemented by positive supercoiling by reverse gyrase [in hyperthermophiles (8, 9, 28)] and by stabilization via interactions with histone-like proteins (29, 30). The relative contribution of base paring and base stacking into the thermostability of double-stranded DNA has been a subject of extensive studies for more than four decades (1, 27, 31). We will consider here this question, based on the results of recent experimental and computational works (31, 32). 

As we have previously outlined, histones are small nuclear proteins that contribute to pack the DNA within nucleosomes (7,33). Histones are subject to a number of covalent post-translational modifications that collectively influence chromatin remodeling and gene expression. The question now is how to build genome-wide histone-maps. The answer came recently thanks to the combination of ChIP followed by either microarrays (ChIP-chip) or sequencing methods (ChIP-Seq) (31). 

Notably, the model generated contains one factor, E2F that is known to be involved in cell cycle regulation of genes [67]. The model appears to be very selective and only one match per 12 million base pairs of the mammalian sections of the EMBL database was found. Almost all matches (total of 59) are known Histone HI genes, except in the human section where the majority of matches (25) are within anonymous sequences. However, given the extraordinary specificity throughout the mammalian sections, it seems safe to assume that most of the unknown matches within the human database section actually identified new so far unannotated genes, that are subject to... 

Histones are subject to the folowing covalent modifications (Fig. 1.33 review Lee and Young, 2000) ... 

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