Figure 4–38 Schematic diagram showing how a particular combination of histone modifications can be recognized by a reader complex. A large protein complex that contains a series of protein modules, each of which recognizes a specific histone mark, is schematically illustrated (green). This “reader complex” will bind tightly only to a region of chromatin that contains several of the different histone marks that it recognizes. Therefore, only a specific combination of marks will cause the complex to bind to chromatin and attract the additional protein complexes (purple) needed to catalyze a biological function.
Figure 4–39 Some specific meanings of histone modifications. (A) The modifications on the histone H3 N-terminal tail are shown, repeated from Figure 4–34. (b) The H3 tail can be marked by different sets of modifications that act in combination to convey a specific meaning. Only a small number of the meanings are known, including the three examples shown. Not illustrated is the fact that, as just implied (see Figure 4–38), reading a histone mark generally involves the joint recognition of marks at other sites on the nucleosome along with the indicated H3 tail recognition. In addition, specific levels of methylation (mono-, di-, or trimethyl groups) are generally required. Thus, for example, the trimethylation of lysine 9 attracts the heterochromatin-specific protein HP1, which induces a spreading wave of further lysine 9 trimethylation followed by further HP1 binding, according to the general scheme that will be illustrated shortly (see Figure 4–40). Also important in this process, however, is a synergistic trimethylation of the histone H4 N-terminal tail on lysine 20.
4–36), activating an attached writer enzyme and positioning it near an adjacent nucleosome. Through many such read–write cycles, the reader protein can carry the writer enzyme along the DNA—spreading the mark in a hand-over-hand manner along the chromosome (Figure 4–40).
In reality, the process is more complicated than the scheme just described. Both readers and writers are part of a protein complex that is likely to contain multiple readers and writers, and to require multiple marks on the nucleosome to spread. Moreover, many of these reader–writer complexes also contain an ATP-dependent chromatin remodeling protein (see Figure 4–26C), and the reader, writer, and remodeling proteins can work in concert to either decondense or condense long stretches of chromatin as the reader moves progressively along the nucleosome-packaged DNA.
A similar process is used to remove histone modifications from specific regions of the DNA; in this case, an “eraser enzyme,” such as a histone demethylase or his-tone deacetylase, is recruited to the complex. As for the writer complex in Figure 4–40, sequence-specific DNA-binding proteins (transcription regulators) direct where such modifications occur (discussed in Chapter 7).
Some idea of the complexity of the above processes can be derived from the results of genetic screens for genes that either enhance or suppress the spreading and stability of heterochromatin, as manifest in effects on position effect variegation in Drosophila (see Figure 4–32). As pointed out previously, more than 100 such genes are known, and most of them are likely to code for subunits in one or more reader–writer–remodeling protein complexes.
Figure 4–40 How the recruitment of a reader–writer complex can spread chromatin changes along a chromosome. The writer is an enzyme that creates a specific modification on one or more of the four nucleosomal histones. After its recruitment to a specific site on a chromosome by a transcription regulatory protein, the writer collaborates with a reader protein to spread its mark from nucleosome to nucleosome by means of the indicated reader–writer complex. For this mechanism to work, the reader must recognize the same histone modification mark that the writer produces; its binding to that mark can be shown to activate the writer. In this schematic example, a spreading wave of chromatin condensation is thereby induced. Not shown are the additional proteins involved, including an ATP-dependent chromatin remodeling complex required to reposition the modified nucleosomes.