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(A) Known modifications of the four histone core proteins are indicated: Me = methyl group, Ac = acetyl group, P = phosphate, u = ubiquitin. Note that some positions (e.g., lysine 9 of H3) can be modified in more than one way. Most of these modifications add a relatively small molecule onto the histone tails; the exception is ubiquitin, a 76 amino acid protein also used in other cellular processes (see Figure 6-87). The function of ubiquitin in chromatin is not well understood: histone H2B can be modified by a single ubiquitin molecule; H2A can be modified by the addition of several ubiquitins. (B) A histone code hypothesis. Histone tails can be marked by different combinations of modifications. According to this hypothesis, each marking conveys a specific meaning to the stretch of chromatin on which it occurs. Only a few of the meanings of the modifications are known. In Chapter 7, we discuss the way a doubly-acetylated H4 tail is “read” by a protein required for gene expression. In another well-studied case, an H3 tail methylated at lysine 9 is recognized by a set of proteins that create an especially compact form of chromatin, which silences gene expression.

The acetylation of lysine 14 of histone H3 and lysines 8 and 16 of histone H4—usually associated with gene expression—is performed by the type A histone acetylases (HATs) in the nucleus. In contrast, the acetylation of lysines 5 and 12 of histone H4 and a lysine of histone H3 takes place in the cytosol, after the histones have been synthesized but before they have been incorporated into nucleosomes; these modifications are catalyzed by type B HATs. These modified histones are deposited onto DNA after DNA replication (see Figure 5-41), and their acetyl groups are taken off shortly afterwards by histone deacetylases (HDACs). Thus, the acetylation at these positions signals newly replicated chromatin.

Modification of a particular position in a histone tail can take on different meanings depending on other features of the local chromatin structure. For example, the phosphorylation of position 10 of histone H3 is associated not only with the condensation of chromosomes that takes place in mitosis and meiosis but also with the expression of certain genes. Some histone tail modifications are interdependent. For example methylation of H3 position 9 blocks the phosphorylation of H3 position 10, and vice versa.