Through chromosome breakage and rejoining, whether brought about by a natural genetic accident or by experimental artifice, a piece of chromosome that is normally euchromatic can be translocated into the neighborhood of heterochromatin. Remarkably, this often causes silencing—inactivation—of the normally active genes. This phenomenon is referred to as a position effect. It reflects a spreading of the heterochromatic state into the originally euchromatic region, and it has provided important clues to the mechanisms that create and maintain heterochromatin. First recognized in Drosophila, position effects have now been observed in many eukaryotes, including yeasts, plants, and humans.
early in the developing embryo, heterochromatin forms and spreads into neighboring euchromatin to different extents in different cells clone of cells with clone of cells with clone of cells with gene 1 inactive genes 1, 2, and 3 inactive no genes inactivated
Figure 4–31 The cause of position effect variegation in Drosophila. (A) Heterochromatin (green) is normally prevented from spreading into adjacent regions of euchromatin (red) by barrier DNA sequences, which we shall discuss shortly. In flies that inherit certain chromosomal rearrangements, however, this barrier is no longer present. (b) During the early development of such flies, heterochromatin can spread into neighboring chromosomal DNA, proceeding for different distances in different cells. This spreading soon stops, but the established pattern of heterochromatin is subsequently inherited, so that large clones of progeny cells are produced that have the same neighboring genes condensed into heterochromatin and thereby inactivated (hence the “variegated” appearance of some of these flies; see Figure 4–32). Although “spreading” is used to describe the formation of new heterochromatin close to previously existing heterochromatin, the term may not be wholly accurate. There is evidence that during expansion, the condensation of DNA into heterochromatin can “skip over” some regions of chromatin, sparing the genes that lie within them from repressive effects.
In chromosome breakage-and-rejoining events of the sort just described, the zone of silencing, where euchromatin is converted to a heterochromatic state, spreads for different distances in different early cells in the fly embryo. Remarkably, these differences then are perpetuated for the rest of the animal’s life: in each cell, once the heterochromatic condition is established on a piece of chromatin, it tends to be stably inherited by all of that cell’s progeny (Figure 4–31). This remarkable phenomenon, called position effect variegation, was first recognized through a detailed genetic analysis of the mottled loss of red pigment in the fly eye (Figure 4–32). It shares features with the extensive spread of heterochromatin that inactivates one of the two X chromosomes in female mammals. There too, a random process acts in each cell of the early embryo to dictate which X chromosome will be inactivated, and that same X chromosome then remains inactive in all the cell’s progeny, creating a mosaic of different clones of cells in the adult body (see Figure 7–50).
These observations, taken together, point to a fundamental strategy of heterochromatin formation: heterochromatin begets more heterochromatin. This positive feedback can operate both in space, causing the heterochromatic state to spread along the chromosome, and in time, across cell generations, propagating the heterochromatic state of the parent cell to its daughters. The challenge is to explain the molecular mechanisms that underlie this remarkable behavior.