Histone tails covalent modifications

In the nucleosome, the DNA is supercoiled in a left-handed helix over the surface of the disk-shaped histone octamer (Figure 36-2). The majority of core histone proteins interact with the DNA on the inside of the supercoil without protruding, though the amino terminal tails of all the histones probably protrude outside of this structure and are available for regulatory covalent modifications (see Table 36-1). 

One of the most-studied covalent modifications is the acetylation of the lysine residues of histone tails. The acetylation state of lysines of nucleosomal histones modulates chromatin structure and regulates gene transcriptional activity. The balance of lysine acetylation is controlled by the antagonistic action of two enzyme families histone deacetylases (HDACs) and histone acetyltransferases (HATs). In humans there are essentially three main HDAC subclasses [6]. 

Epigenetic is a term used to describe a state of gene expression that is mitotically and meiotically inherited without any change in the sequence of DNA. Epigenetic mechanisms are mainly of two classes (1) the DNA may be modified by the covalent attachment of a moiety that is then perpetuated. (2) a self-perpetuating protein state may be established (Zelent et al, 2004). The two most studied epigenetic phenomena are DNA methylation and histone tail modifications (Mai et ai, 2005). 

Zeng L, Zhou MM (2002) Bromodomain an acetyl-lysine binding domain. EEBS letters 513 124-128 Zhang Y, Reinberg D (2001) Transcription regulation by histone methylation interplay between different covalent modifications of the core histone tails. Genes Dev 15 2343-2360... 

Chromatin-modifying complexes are classified into two major groups (1) enzymes that conttol covalent modifications of the amino-terminal tails of histones (acetylation, methylation, phosphorylation, ubiquitinylation) (see Sections 1.3 and... 

The covalent modifications of histone tails such as acetylation, phosphorylation, and ubiquitination have been shown to be reversible. This reversibility help the cells to respond to these regulatory modifications and thereby, influence the gene expression. Methylation of histones however, has been considered to be a relatively stable and irreversible mark on histones. Nevertheless active turnover of methyl groups on histones do exist. One of the possible mechanism of removal of methyl... 

Although the histone fold was first described from the structure of the histone octamer core of the nucleosome [17], the high a-helical content was predicted much earlier [43]. The core histones possess three functional domains (1) the histone fold domain, (2) an N-terminal tail domain, and (3) various accessory helices and less structured regions. The N-terminal tail domains of the core histones are currently the focus of intense research. Covalent modifications of residues in these unstructured domains appear to modify local chromatin structure, either directly or... 

Chromatin Structure Is Modulated Through Covalent Modifications of Histone Tails... 

Outline the covalent modification and demodification of histone tails. 

Several known covalent modifications have been observed so far that can modify the amino acid residues in the histone tails. There include acetylation, phosphorylation, ubiquitination, and methylation. Although some of these modifications have been known for many years, only recently have functional roles for these modifications begun to surface (Workman and Kingston, 1998). Each histone can undergo numerous modifications, and the combinatorial effect of these serves to elicit a multitude of different responses. This combinatorial modification of histone tails has been referred to as the histone code (Jenuwein and Allis, 2001 Strahl and Allis, 2000) and has been proposed to play a pivotal role in the regulation of gene expression (Fig. 3). 

Higher-order chromatin is essential for epigenetic gene control and for the functional organization of chromosomes. Differences in higher-ordered chromatin structure are linked with distinct covalent modifications of histone tails that regulate transcriptional on or off states, and influence chromosome condensation and segregation. Post-translational modifications of histone N-termini, particularly of H4 and H3, are well documented and have... 

Chromatin is made of repetitive nucleoprotein complexes, the nucleosomes (Wolffe 1998). The Ai-terminal tails of core histones protrude from the nucleosomal surface. Covalent modifications of these tails affect the structure of chromatin and are crucial for gene regulation by epigenetic mechanisms. Some modifications also exist in the globular domain and C-terminal regions (Kouzarides and Berger 2007 Zempleni et al. 2009) (Figure 10.3). 

Finally, 1964 saw the publication of a discovery whose impact resonated only in 1996, but quite emphatically the observation by V. Allfrey, and A. E. Mirsky that histone proteins are subjected to postranslational covalent modification via the acetylation and methylation of lysine residues in their NH2-terminal tails (Sections IV.A and IV.C). Because the modifications reduce the positive charge of the histones (and thus have the potential to alter the way histones interact with DNA), it was immediately suspected they might have regulatory consequences. Conclusive evidence to that effect was obtained in 1998 (Section IV.C). 

An additional important observation on the )3-globin locus related to a different type of chromatin structure alteration observed in vivo a change in the covalent modification status of histone tails within a domain of transcriptionally active chromatin. To better illuminate the significance of this finding, we must briefly review the biochemistry of such modifications. As mentioned earlier, in 1964 it was discovered that particular lysine residues in the NH2-terminal tails of the core histones are reversibly covalently modified by acetylation ... 

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