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

MECHANISMS THAT REINFORCE CELL MEMORY IN PLANTS AND ANIMALS
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Figure 7–51 Photoreceptor cells in the retina of a female mouse showing
patterns of X-chromosome inactivation. Using genetic engineering
techniques (described in Chapter 8), the germ line of a mouse was modified
so that one copy of the X chromosome (if active) makes a green fluorescent
protein and the other a red fluorescent protein. Both proteins concentrate in
the nucleus and, in the field of cells shown here, it is clear that only one of
the two X chromosomes is active in each cell. (From H. Wu et al., Neuron
81:103–119, 2014. With permission from Elsevier.)
distributed in small clusters in the adult animal because sister cells tend to remain
close together during later stages of development (Figure 7–51). For example,
X-chromosome inactivation causes the orange and black “tortoiseshell” coat
coloration of some female cats. In these cats, one X chromosome carries a gene
that produces orange hair color, and the other X chromosome carries an allele
of the same gene that results in black hair color; it is the random X-inactivation
that produces patches of cells of two distinctive colors. In contrast, male cats of
this genetic stock are either solid orange or solid black, depending on which X
chromosome they inherit from their mothers. Although X-chromosome inactivation
is maintained over thousands of cell divisions, it is reversed during germ-cell
formation, so that all haploid oocytes contain an active X chromosome and can
express X-linked gene products.
How is an entire chromosome transcriptionally inactivated? X-chromosome
inactivation is initiated and spreads from a single site near the middle of the X
chromosome, the X-inactivation center (XIC). Within the XIC is a transcribed
20,000-nucleotide lncRNA (called Xist), which is expressed solely from the inactive
X chromosome. Xist RNA spreads from the XIC over the entire chromosome
and directs gene silencing. Although we do not know exactly how this is accomplished,
it likely involves recruitment of histone-modifying enzymes and other
proteins to form a repressive form of chromatin analogous to that of Figure 7–45.
Curiously, about 10% of the genes on the X chromosome (including Xist itself)
escape this silencing and remain active.
The spread of Xist RNA along the X chromosome does not proceed linearly
along the DNA. Rather, starting at its site of synthesis, it is first handed off across
the base of the DNA loops that make up the chromosome; these shortcuts explain
how Xist can spread rapidly, by a “hand-over-hand” mechanism, along the X
chromosome once the inactivation process begins (Figure 7–52). It also helps to
explain why the inactivation does not spread to the other, active X chromosome.
Imprinting and X-chromosome inactivation are examples of monoallelic gene
expression, where in a diploid genome, only one of the two copies of a gene is
expressed. In addition to the approximately 1000 genes on the X chromosome and
the 300 or so genes that are imprinted, there are another 1000–2000 human genes
that exhibit monoallelic expression. Like X-chromosome inactivation (but unlike
imprinting), the choice of which copy of the gene is to be expressed and which is
to be silenced often appears random. Yet once the choice is made, it can persist for
many cell divisions. Because the choice is often made relatively late in development,
cells of the same tissue in the same individual can express different copies
of a given gene. In other words, somatic tissues are often mosaics, where different
clones of cells have subtly different patterns of gene expression. The mechanisms
responsible for this type of monoallelic expression are not known in detail, and
its general purpose—if any—is poorly understood. Several different mechanisms
may contribute to such epigenetic inheritance, as we explain next.
MBoC6 n7.501/7.
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Epigenetic Mechanisms Ensure That Stable Patterns of Gene
Expression Can Be Transmitted to Daughter Cells
As we have seen, once a cell in an organism differentiates into a particular cell
type, it generally remains specialized in that way; if it divides, its daughters inherit
the same specialized character. Perhaps the simplest way for a cell to remember