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

206 Chapter 4: DNA, Chromosomes, and Genomes
blastulastage
embryos
donor Xenopus
embryo
inject normal
H3.3 mRNA
no injection
(control)
somite cells expressing MyoD
nuclear transfer
enucleated egg
two-cell stage embryo
inject mutant
H3.3 mRNA
cells analyzed for MyoD expression and for H3.3 histone on MyoD promoter
HIGH MyoD
EPIGENETIC
MEMORY
(much MyoD
protein
produced)
MODERATE MyoD
EPIGENETIC
MEMORY
LOW MyoD
EPIGENETIC
MEMORY
(little MyoD
protein
produced)
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
MBoC6
type can
n4.105/4.45
be converted into another.
Figure 4–45 Evidence for the inheritance
of a gene-activating chromatin state.
The well-characterized MyoD gene
encodes a master transcription regulatory
protein for muscle, MyoD (see p. 399). This
gene is normally turned on in the indicated
region of the young embryo where somites
form. When a nucleus from this region is
injected into an enucleated egg as shown,
many of the progeny cell nuclei abnormally
express the MyoD protein in non-muscle
regions of the “nuclear transplant embryo”
that forms. This abnormal expression can
be attributed to maintenance of the MyoD
promoter region in its active chromatin
state through the many cycles of cell
division that produce the blastula-stage
embryo—a so-called “epigenetic memory”
that persists in this case in the absence
of transcription. The active chromatin
surrounding the MyoD promoter contains
the variant histone H3.3 (see Figure 4–35)
in a Lys4 methylated form. As indicated,
an overproduction of this histone caused
by injecting excess mRNA encoding the
normal H3.3 protein increases both H3.3
occupancy on the MyoD promoter and
the epigenetic MyoD production, whereas
injection of an mRNA producing a mutant
form of H3.3 that cannot be methylated
at Lys4 reduces the epigenetic MyoD
production. Such experiments provide
evidence that an inherited chromatin state
underlies the epigenetic memory observed.
(Adapted from R.K. Ng and J.B. Gurdon,
Nat. Cell Biol. 10:102–109, 2008. With
permission from Macmillan Publishers Ltd.)
Chromatin Structures Are Important for Eukaryotic Chromosome
Function
Although a great deal remains to be learned about the functions of different chromatin
structures, the packaging of DNA into nucleosomes was probably crucial
for the evolution of eukaryotes like ourselves. To form a complex multicellular
organism, the cells in different lineages must specialize by changing the accessibility
and activity of many hundreds of genes. As described in Chapter 21, this
process depends on cell memory: each cell holds a record of its past developmental
history in the regulatory circuits that control its many genes. That record, it
seems, is partly stored in the structure of the chromatin.
Although bacteria also have cell memory mechanisms, the complexity of the
memory circuits in higher eukaryotes is unparalleled. Strategies based on local
variations in chromatin structure, unique to eukaryotes, can enable individual
genes, once they are switched on or switched off, to stay in that state until some
new factor acts to reverse it. At one extreme are structures like centromeric chromatin
that, once established, are stably inherited from one cell generation to the
next. Likewise, the major “classical” type of heterochromatin, which contains long
arrays of the HP1 protein (see Figure 4–39), can persist stably throughout life. In
contrast, a form of condensed chromatin that is created by the Polycomb group of
proteins serves to silence genes that must be kept inactive in some conditions, but
are active in others. The latter mechanism governs the expression of a large number
of genes that encode transcription regulators important in early embryonic
development, as discussed in Chapter 21. There are many other variant forms of
chromatin, some with much shorter lifetimes, often less than the division time of
the cell. We shall say more about the variety of chromatin types in the next section.