Figure 4–43 evidence for the plasticity of human centromere formation. (A) A series of A-T-rich alpha satellite DNA sequences is repeated many thousands of times at each human centromere (red), and is surrounded by pericentric heterochromatin (brown). However, due to an ancient chromosome breakage-and-rejoining event, some human chromosomes contain two blocks of alpha satellite DNA, each of which presumably functioned as a centromere in its original chromosome. Usually, chromosomes with two functional centromeres are not stably propagated because they attach improperly to the spindle and are broken apart during mitosis. In chromosomes that do survive, however, one of the centromeres has somehow become inactivated, even though it contains all the necessary DNA sequences. This allows the chromosome to be stably propagated. (b) In a small fraction (1/2000) of human births, extra chromosomes are observed in cells of the offspring. Some of these extra chromosomes, which have formed from a breakage event, lack alpha satellite DNA altogether, yet new centromeres (neocentromeres) have arisen from what was originally euchromatic DNA.
The complexity of centromeric chromatin is not illustrated in these diagrams. The alpha satellite DNA that forms centromeric chromatin in humans is packaged into alternating blocks of chromatin. One block is formed from a long string of nucleosomes containing the CENP-A H3 variant histone; the other block contains nucleosomes that are specially marked with dimethyl lysine 4 on the normal H3 histone. Each block is more than a thousand nucleosomes long. This centromeric chromatin is flanked by pericentric heterochromatin, as shown. The pericentric chromatin contains methylated lysine 9 on its H3 histones, along with HP1 protein, and it is an example of “classical” heterochromatin (see Figure 4–39).
related, often have different numbers of chromosomes; see Figure 4–14 for an extreme example. As we shall discuss below, detailed genome comparisons show that in many cases the changes in chromosome numbers have arisen through chromosome breakage-and-rejoining events, creating novel chromosomes, some of which must initially have contained abnormal numbers of centromeres—either more than one, or none at all. Yet stable inheritance requires that each chromosome should contain one centromere, and one only. It seems that surplus centromeres must have been inactivated, and/or new centromeres created, so as to allow the rearranged chromosome sets to be stably maintained.
The changes in centromere activity just discussed, once established, need to be perpetuated through subsequent cell generations. What could be the mechanism of this type of epigenetic inheritance?
It has been proposed that de novo centromere formation requires an initial seeding event, involving the formation of a specialized DNA–protein structure that contains nucleosomes formed with the CENP-A variant of histone H3. In humans, this seeding event happens more readily on arrays of alpha satellite DNA than on other DNA sequences. The H3–H4 tetramers from each nucleosome on the parental DNA helix are directly inherited by the sister DNA helices at a replication fork (see Figure 5–32). Therefore, once a set of CENP-A-containing nucleosomes has been assembled on a stretch of DNA, it is easy to understand how a new centromere could be generated in the same place on both daughter chromosomes following each round of cell division. One need only assume that the presence of the CENP-A histone in an inherited nucleosome selectively recruits more CENP-A histone to its newly formed neighbors.