Figure 4–29 A model for the role played by histone tails in the compaction of chromatin. (A) A schematic diagram shows the approximate exit points of the eight histone tails, one from each histone protein, that extend from each nucleosome. The actual structure is shown to its right. In the high-resolution structure of the nucleosome, the tails are largely unstructured, suggesting that they are highly flexible. (b) As indicated, the histone tails are thought to be involved in interactions between nucleosomes that help to pack them together. (A, PDb code: 1k X5.)
Figure 4–30 How the linker histone binds to the nucleosome. The position and structure of histone H1 is shown. The H1 core region constrains an additional 20 nucleotide pairs of DNA where it exits from the nucleosome core and is important for compacting chromatin. (A) Schematic, and (b) structure inferred for a single nucleosome from a structure determined by high-resolution electron microscopy of a reconstituted chromatin fiber (C). (b and C, adapted from F. Song et al., Science 344:376–380, 2014.)
Having described how DNA is packaged into nucleosomes to create a chromatin fiber, we now turn to the mechanisms that create different chromatin structures in different regions of a cell’s genome. Mechanisms of this type have a variety of important functions in cells. Most strikingly, certain types of chromatin structure can be inherited; that is, the structure can be directly passed down from a cell to its descendants. Because the cell memory that results is based on an inherited chromatin structure rather than on a change in DNA sequence, this is a form of epigenetic inheritance. The prefix epi is Greek for “on”; this is appropriate, because epigenetics represents a form of inheritance that is superimposed on the genetic inheritance based on DNA.
In Chapter 7, we shall introduce the many different ways in which the expression of genes is regulated. There we discuss epigenetic inheritance in detail and present several different mechanisms that can produce it. Here, we are concerned with only one, that based on chromatin structure. We begin this section by reviewing the observations that first demonstrated that chromatin structures can be inherited. We then describe some of the chemistry that makes this possible— the covalent modification of histones in nucleosomes. These modifications have many functions, inasmuch as they serve as recognition sites for protein domains that link specific protein complexes to different regions of chromatin. Histones thereby have effects on gene expression, as well as on many other DNA-linked processes. Through such mechanisms, chromatin structure plays an important role in the development, growth, and maintenance of all eukaryotic organisms, including ourselves.
Light-microscope studies in the 1930s distinguished two types of chromatin in the interphase nuclei of many higher eukaryotic cells: a highly condensed form, called heterochromatin, and all the rest, which is less condensed, called euchromatin. Heterochromatin represents an especially compact form of chromatin (see Figure 4–9), and we are finally beginning to understand its molecular properties. It is highly concentrated in certain specialized regions, most notably at the centromeres and telomeres introduced previously (see Figure 4–19), but it is also present at many other locations along chromosomes—locations that can vary according to the physiological state of the cell. In a typical mammalian cell, more than 10% of the genome is packaged in this way.
The DNA in heterochromatin typically contains few genes, and when euchromatic regions are converted to a heterochromatic state, their genes are generally switched off as a result. However, we know now that the term heterochromatin encompasses several distinct modes of chromatin compaction that have different implications for gene expression. Thus, heterochromatin should not be thought of as simply encapsulating “dead” DNA, but rather as a descriptor for compact chromatin domains that share the common feature of being unusually resistant to gene expression.
The Heterochromatic State Is Self-Propagating