Figure 4–36 How a mark on a nucleosome is read. The figure shows the structure of a protein module (called an INg PHD domain) that specifically recognizes histone H3 trimethylated on lysine 4. (A) A trimethyl group. (b) Space-filling model of an INg PHD domain bound to a histone tail (green, with the trimethyl group highlighted in yellow). (C) A ribbon model showing how the N-terminal six amino acids in the H3 tail are recognized. The red lines represent hydrogen bonds. This is one of a family of PHD domains that recognize methylated lysines on histones; different members of the family bind tightly to lysines located at different positions, and they can discriminate between a mono-, di-, and trimethylated lysine. In a similar way, other small protein modules recognize specific histone side chains that have been marked with acetyl groups, phosphate groups, and so on. (Adapted from P.v. Peña et al., Nature 442:100–103, 2006. with permission from macmillan Publishers ltd.) protein or protein complex, which thereby recognizes a specific combination of histone modifications (Figure 4–37). The result is a reader complex that allows particular combinations of markings on chromatin to attract additional proteins, so as to execute an appropriate biological function at the right time (Figure 4–38).
The marks on nucleosomes due to covalent additions to histones are dynamic, being constantly removed and added at rates that depend on their chromosomal locations. Because the histone tails extend outward from the nucleosome core and are likely to be accessible even when chromatin is condensed, they would seem to provide an especially suitable format for creating marks that can be readily altered as a cell’s needs change. Although much remains to be learned about the meaning of the different histone modifications, a few well-studied examples of the information that can be encoded in the histone H3 tail are listed in Figure 4–39.
A Complex of Reader and writer Proteins Can Spread Specific
The phenomenon of position effect variegation described previously requires that some modified forms of chromatin have the ability to spread for substantial distances along a chromosomal DNA molecule (see Figure 4–31). How is this possible?
The enzymes that add or remove modifications to histones in nucleosomes are part of multisubunit complexes. They can initially be brought to a particular region of chromatin by one of the sequence-specific DNA-binding proteins (transcription regulators) discussed in Chapters 6 and 7 (for a specific example,
Figure 4–37 Recognition of a specific combination of marks on a nucleosome. In the example shown, two adjacent domains that are part of the NURF (Nucleosome Remodeling Factor) chromatin remodeling complex bind to the nucleosome, with the PHD domain (red) recognizing a methylated H3 lysine 4 and another domain (a bromodomain, blue) recognizing an acetylated H4 lysine 16. These two histone marks constitute a unique histone modification pattern that occurs in subsets of nucleosomes in human cells. Here the two histone tails are indicated by green dotted lines, and only half of one nucleosome is shown. (Adapted from A.J. Ruthenburg et al., Cell 145:692–706, 2011. with permission from Elsevier.) protein modules scaffold binding to specifc protein histone modifcations on nucleosome attachment to other components in nucleus, leading to gene expression, gene silencing, or other biological function see Figure 7–20). But after a modifying enzyme “writes” its mark on one or a few neighboring nucleosomes, events that resemble a chain reaction can ensue. In such a case, the “writer enzyme” works in concert with a “reader protein” located in the same protein complex. The reader protein contains a module that recognizes the mark and binds tightly to the newly modified nucleosome (see Figure heterochromatin formation, gene silencingK 9