Epigenetic effects can be inherited

More Information About This Text

Epigenetic effects can be inherited

Epigenetic changes influence the phenotype without altering the genotype. They consist of changes in the properties of a cell that are inherited but that do not represent a change in genetic information.

Epigenetic effects can result from modification of a nucleic acid after it has been synthesized or by the perpetuation of protein structures.

Epigenetic inheritance describes the ability of different states, which may have different phenotypic consequences, to be inherited without any change in the sequence of DNA. How can this occur?

We can divide epigenetic mechanisms into two general classes:

DNA may be modified by the covalent attachment of a moiety that is then perpetuated. Two alleles with the same sequence may have different states of methylation that confer different properties.
Or a self perpetuating protein state may be established. This might involve assembly of a protein complex, modification of specific protein(s), or establishment of an alternative protein conformation.

Methylation establishes epigenetic inheritance so long as the maintenance methylase acts constitutively to restore the methylated state after each cycle of replication, as shown in Figure 23.36. A state of methylation can be perpetuated through an indefinite series of somatic mitoses. This is probably the "default" situation. Methylation can also be perpetuated through meiosis: for example, in the fungus Ascobolus there are epigenetic effects that can be transmitted through both mitosis and meiosis by maintaining the state of methylation. In mammalian cells, epigenetic effects are created by resetting the state of methylation differently in male and female meioses.

Situations in which epigenetic effects appear to be maintained by means of protein states are less well understood in molecular terms. Position effect variegation shows that constitutive heterochromatin may extend for a variable distance, and the structure is then perpetuated through somatic divisions. Since there is no methylation of DNA in Saccharomyces and a vanishingly small amount in Drosophila, the inheritance of epigenetic states of position effect variegation or telomeric silencing in these organisms is likely to be due to the perpetuation of protein structures.

Figure 23.42

What happens to protein complexes on chromatin during replication?

Figure 23.42 considers two extreme possibilities for the fate of a protein complex at replication.

A complex could perpetuate itself if it splits symmetrically, so that half complexes associate with each daughter duplex. If the half complexes have the capacity to nucleate formation of full complexes, the original state will be restored. This is basically analogous to the maintenance of methylation. The problem with this model is that there is no evident reason why protein complexes should behave in this way.
A complex could be maintained as a unit and segregate to one of the two daughter duplexes. The problem with this model is that it requires a new complex to be assembled de novo on the other daughter duplex, and it is not evident why this should happen.

Consider now the need to perpetuate a heterochromatic structure consisting of protein complexes. Suppose that a protein is distributed more or less continuously along a stretch of heterochromatin, as implied in Figure 23.20. If individual subunits are distributed at random to each daughter duplex at replication, the two daughters will continue to be marked by the protein, although its density will be reduced to half of the level before replication. If the protein has a self-assembling property that causes new subunits to associate with it, the original situation may be restored. Basically, the existence of epigenetic effects forces us to the view that a protein responsible for such a situation must have some sort of self-templating or self-assembling capacity.

In some cases, it may be the state of protein modification, rather than the presence of the protein per se, that is responsible for an epigenetic effect. There is a general correlation between the activity of chromatin and the state of acetylation of the histones, in particular the acetylation of histones H3 and H4, which occurs on their N-terminal tails. Activation of transcription is associated with acetylation in the vicinity of the promoter; and repression of transcription is associated with deacetylation (see Acetylases are associated with activators). The most dramatic correlation is that the inactive X chromosome in mammalian female cells is underacetylated on histone H4.

The inactivity of constitutive heterochromatin may require that the histones are not acetylated. If a histone acetyltransferase is tethered to a region of telomeric heterochromatin in yeast, silenced genes become active. When yeast is exposed to trichostatin (an inhibitor of deacetylation), centromeric heterochromatin becomes acetylated, and silenced genes in centromeric regions may become active. The effect may persist even after trichostatin has been removed. In fact, it may be perpetuated through mitosis and meiosis. This suggests that an epigenetic effect has been created by changing the state of histone acetylation.

Figure 23.43

Acetylated cores are conserved and distributed at random to the daughter chromatin fibers at replication. Each daughter fiber has a mixture of old (acetylated) cores and new (unacetylated) cores.

How might the state of acetylation be perpetuated? Suppose that the H3₂•H4₂ tetramer is distributed at random to the two daughter duplexes. This creates the situation shown in Figure 23.43, in which each daughter duplex contains some histone octamers that are fully acetylated on the H3 and H4 tails, while others are completely unacetylated. To account for the epigenetic effect, we could suppose that the presence of some fully acetylated histone octamers provides a signal that causes the unacetylated octamers to be acetylated.

(The actual situation is probably more complicated than shown in the figure, because transient acetylations occur during replication. If they are simply reversed following deposition of histones into nucleosomes, they may be irrelevant. An alternative possibility is that the usual deacetylation is prevented, instead of, or as well as, inducing acetylation.)

Instructors: More Information About This Text | Jones and Bartlett Biological Science Titles