Although a great deal remains to be learned about the functions of different chromatin structures, the packaging of DNA into nucleosomes was probably crucial for the evolution of eukaryotes like ourselves. To form a complex multicellular organism, the cells in different lineages must specialize by changing the accessibility and activity of many hundreds of genes. As described in Chapter 21, this process depends on cell memory: each cell holds a record of its past developmental history in the regulatory circuits that control its many genes. That record, it seems, is partly stored in the structure of the chromatin.
Although bacteria also have cell memory mechanisms, the complexity of the memory circuits in higher eukaryotes is unparalleled. Strategies based on local variations in chromatin structure, unique to eukaryotes, can enable individual genes, once they are switched on or switched off, to stay in that state until some new factor acts to reverse it. At one extreme are structures like centromeric chromatin that, once established, are stably inherited from one cell generation to the next. Likewise, the major “classical” type of heterochromatin, which contains long arrays of the HP1 protein (see Figure 4–39), can persist stably throughout life. In contrast, a form of condensed chromatin that is created by the Polycomb group of proteins serves to silence genes that must be kept inactive in some conditions, but are active in others. The latter mechanism governs the expression of a large number of genes that encode transcription regulators important in early embryonic development, as discussed in Chapter 21. There are many other variant forms of chromatin, some with much shorter lifetimes, often less than the division time of the cell. We shall say more about the variety of chromatin types in the next section.
Figure 4–45 evidence for the inheritance of a gene-activating chromatin state.
The well-characterized MyoD gene encodes a master transcription regulatory protein for muscle, myoD (see p. 399). This gene is normally turned on in the indicated region of the young embryo where somites form. when a nucleus from this region is injected into an enucleated egg as shown, many of the progeny cell nuclei abnormally express the myoD protein in non-muscle regions of the “nuclear transplant embryo” that forms. This abnormal expression can be attributed to maintenance of the MyoD promoter region in its active chromatin state through the many cycles of cell division that produce the blastula-stage embryo—a so-called “epigenetic memory” that persists in this case in the absence of transcription. The active chromatin surrounding the MyoD promoter contains the variant histone H3.3 (see Figure 4–35) in a lys4 methylated form. As indicated, an overproduction of this histone caused by injecting excess mRNA encoding the normal H3.3 protein increases both H3.3 occupancy on the MyoD promoter and the epigenetic myoD production, whereas injection of an mRNA producing a mutant form of H3.3 that cannot be methylated at lys4 reduces the epigenetic myoD production. Such experiments provide evidence that an inherited chromatin state underlies the epigenetic memory observed. (Adapted from R.k. Ng and J.b. gurdon, Nat. Cell Biol. 10:102–109, 2008. with permission from macmillan Publishers ltd.)
In the chromosomes of eukaryotes, DNA is uniformly assembled into nucleosomes, but a variety of different chromatin structures is possible. This variety is based on a large set of reversible covalent modifications of the four histones in the nucleosome core. These modifications include the mono-, di-, and trimethylation of many different lysine side chains, an important reaction that is incompatible with the acetylation that can occur on the same lysines. Specific combinations of the modifications mark many nucleosomes, governing their interactions with other proteins. These marks are read when protein modules that are part of a larger protein complex bind to the modified nucleosomes in a region of chromatin. These reader proteins then attract additional proteins that perform various functions.