In addition to the four highly conserved standard core histones, eukaryotes also contain a few variant histones that can also assemble into nucleosomes. These histones are present in much smaller amounts than the major histones, and they have been less well conserved over long evolutionary times. Variants are known for each of the core histones with the exception of H4; some examples are shown in Figure 4–35.
The major histones are synthesized primarily during the S phase of the cell cycle and assembled into nucleosomes on the daughter DNA helices just behind the replication fork (see Figure 5–32). In contrast, most histone variants are synthesized throughout interphase. They are often inserted into already-formed chromatin, which requires a histone-exchange process catalyzed by the ATP-dependent chromatin remodeling complexes discussed previously. These remodeling complexes contain subunits that cause them to bind both to specific sites on chromatin and to histone chaperones that carry a particular variant. As a result, each histone variant is inserted into chromatin in a highly selective manner (see Figure 4–27).
Covalent modifications and Histone variants Act in Concert to Control Chromosome Functions
The number of possible distinct markings on an individual nucleosome is in principle enormous, and this potential for diversity is still greater when we allow for nucleosomes that contain histone variants. However, the histone modifications are known to occur in coordinated sets. More than 15 such sets can be identified in mammalian cells. However, it is not yet clear how many different types of chromatin are functionally important in cells.
Some combinations are known to have a specific meaning for the cell in the sense that they determine how and when the DNA packaged in the nucleosomes is to be accessed or manipulated—a fact that led to the idea of a “histone code.” For example, one type of marking signals that a stretch of chromatin has been newly replicated, another signals that the DNA in that chromatin has been damaged and needs repair, while others signal when and how gene expression should take place. Various regulatory proteins contain small domains that bind to specific marks, recognizing, for example, a trimethylated lysine 4 on histone H3 (Figure 4–36). These domains are often linked together as modules in a single large
Figure 4–35 The structure of some histone variants compared with the major histone that they replace. The histone variants are inserted into nucleosomes at specific sites on chromosomes by ATP-dependent chromatin remodeling enzymes that act in concert with histone chaperones (see Figure 4–27). The CENP-A (Centromere Protein-A) variant of histone H3 is discussed later in this chapter (see Figure 4–42); other variants are discussed in Chapter 7. The sequences in each variant that are colored differently (compared to the major histone above it) denote regions with an amino acid sequence different from this major histone. (Adapted from k. Sarma and D. Reinberg, Nat. Rev. Mol. Cell Biol. 6:139–149, 2005. with permission from macmillan Publishers ltd.)