Histone hypothesis

The aim of this article is to present evidence and to develop a hypothesis concerning the dynamic structural role of histones in chromatin. 

In contrast to simple charge neutralization effects, the effects on protein recog-nition/recruitment are collectively referred to as the histone code . This hypothesis predicts that specific patterns of histone tail acetylations and other modifications serve as epigenetic marks for distinct sets of regulatory proteins to differentially modulate chromatin structure and function (Strahl and Allis, 2000 Turner, 2000 Jenuwein and Allis, 2001). Indeed, several recent findings have demonstrated that histone acetylation creates a signal for the binding of a bromodomain which has... 

Realini and Althaus [313] have put forth the hypothesis that poly(ADP-ribosylation) may have a function in histone shuttling. They propose that poly(ADP-ribose) polymerase directed to sites of DNA strand breaks would auto-modify itself generating multiple ADP-ribose polymers. The polymers would lead to the dissociation of the histones from DNA onto the polymers. The DNA would now be free for processing (e.g., by enzymes involved in excision repair). The action of poly(ADP-ribose) glycohydrolase would degrade the... 

Regardless of the loeal or global nature of histone acetylation, how these two elfects alfect chromatin structure still remains an open question. As it will be discussed in Section 6.2, proving the initial hypothesis that histone acetylation weakens the histone-DNA interactions in a way that facilitates chromatin unfolding has not been that simple. 

A significant portion of the histone variability described in the previous sections affects the electrostatic charge or hydrophobic character of these proteins particularly at the N- and C-terminal regions of the molecule. While some of these modifications appear to be used as a coding mechanism [121,123,165] (see histone code hypothesis, Fig. 5), the changes in the polarity also most likely play an additionally important role in the modulation of the histone-DNA... 

Yet another hypothesis considers the somatic variant Hle of histone HI, in its poly(ADP-ribosyl)ated isoform, as a nuclear traw -acting factor involved in maintaining the methylation pattern on DNA [161]. 

He, S. et al. (2003) Facile synthesis of site-specifically acetylated and methylated histone proteins reagents for evaluation of ihe histone code hypothesis. Proceedings of the National Academy of Sciences of the United States of America, 100, 12033-12038. 

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]. 

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