Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

CHROMATIN STRUCTURE AND FUNCTION
195
1 2 3 4 5
1 2 3 4 5
1 2 3 4 5
heterochromatin
barrier
euchromatin
genes
1 2 3 4 5
early in the developing embryo, heterochromatin forms and spreads into neighboring
euchromatin to different extents in different cells
CHROMOSOME
TRANSLOCATION
1 2 3 4 5
1 2 3 4 5
1 2 3 4 5
cell proliferation
1 2 3 4 5
heterochromatin
euchromatin
clone of cells with
gene 1 inactive
clone of cells with
genes 1, 2, and 3 inactive
clone of cells with
no genes inactivated
(A)
(B)
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,
MBoC6 m4.36/4.29
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.
White gene
at normal
location
barrier
barrier
rare chromosome
inversion
White gene
near heterochromatin
heterochromatin
Figure 4–32 The discovery of position
effects on gene expression. The White
gene in the fruit fly Drosophila controls eye
pigment production and is named after the
mutation that first identified it. Wild-type
flies with a normal White gene (White + )
have normal pigment production, which
gives them red eyes, but if the White gene
is mutated and inactivated, the mutant
flies (White – ) make no pigment and have
white eyes. In flies in which a normal White
gene has been moved near a region of
heterochromatin, the eyes are mottled,
with both red and white patches. The white
patches represent cell lineages in which
the White gene has been silenced by the
effects of the heterochromatin. In contrast,
the red patches represent cell lineages in
which the White gene is expressed. Early
in development, when the heterochromatin
is first formed, it spreads into neighboring
euchromatin to different extents in different
embryonic cells (see Figure 4–31). The
presence of large patches of red and white
cells reveals that the state of transcriptional
activity, as determined by the packaging of
this gene into chromatin in those ancestor
cells, is inherited by all daughter cells.