There are some striking similarities between the formation and maintenance of centromeres and the formation and maintenance of some other regions of heterochromatin. In particular, the entire centromere forms as an all-or-none entity, suggesting that the creation of centromeric chromatin is a highly cooperative process, spreading out from an initial seed in a manner reminiscent of the phenomenon of position effect variegation that we discussed earlier. In both cases, a particular chromatin structure, once formed, seems to be directly inherited on the DNA following each round of chromosome replication. A cooperative recruitment of proteins, along with the action of reader–writer complexes, can thus not only account for the spreading of specific forms of chromatin in space along the chromosome, but also for its propagation across cell generations—from parent cell to daughter cell (Figure 4–44).
Experiments with Frog Embryos Suggest that both Activating and Repressive Chromatin Structures Can be Inherited Epigenetically
Epigenetic inheritance plays a central part in the creation of multicellular organisms. Their differentiated cell types become established during development, and persist thereafter even through repeated cell-division cycles. The daughters of a liver cell persist as liver cells, those of an epidermal cell as epidermal cells, and so on, even though they all contain the same genome; and this is because distinctive patterns of gene expression are passed on faithfully from parent cell to daughter cell. Chromatin structure has a role in this epigenetic transmission of information from one cell generation to the next.
One type of evidence comes from studies in which the nucleus of a cell from a frog or tadpole is transplanted into a frog egg whose own nucleus has been removed (an enucleated egg). In a classic set of experiments performed in 1968, it was shown that a nucleus taken from a differentiated donor cell can be reprogrammed in this way to support development of a whole new tadpole (see Figure 7–2). But this reprogramming occurs only with difficulty, and it becomes less and less efficient as nuclei from older animals are used. Thus, for example, less than 2% of the enucleated eggs injected with a nucleus from a tadpole epithelial cell developed to the swimming tadpole stage, compared with 35% when the donor nuclei were taken instead from an early (gastrula-stage) embryo. With new experimental tools, the cause of this resistance to reprogramming can now be traced. It arises, at least in part, because specific chromatin structures in the original differentiated nucleus tend to persist and be transmitted through the many cell-division cycles required for embryonic development. In experiments with Xenopus embryos, specific forms of either repressive or active chromatin structures could be demonstrated to persist through as many as 24 cell divisions, causing the misplaced expression of genes. Figure 4–45 briefly describes one such experiment,
Figure 4–44 How the packaging of DNA in chromatin can be inherited following chromosome replication.
In this model, some of the specialized chromatin components are distributed to each sister chromosome after DNA duplication, along with the specially marked nucleosomes that they bind. After DNA replication, the inherited nucleosomes that are specially modified, acting in concert with the inherited chromatin components, change the pattern of histone modification on the newly formed nucleosomes nearby. This creates new binding sites for the same chromatin components, which then assemble to complete the structure. The latter process is likely to involve reader– writer–remodeling complexes operating in a manner similar to that previously illustrated in Figure 4–40.
inject normal no injection inject mutant H3.3 mRNA (control) H3.3 mRNA cells analyzed for MyoD expression and for H3.3 histone on MyoD promoter focused on chromatin containing the histone variant, H3.3. We shall return to these phenomena in the final section of Chapter 22, where we discuss stem cells and the ways in which one cell type can be converted into another.