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The molecular mechanism
of X chromosome inactivation,
presented
by Professor Neil Brockdorff
of the Department
of Biochemistry,
University of Oxford.
I'll begin my talk
with a short introduction
followed by a discussion
of critical steps
in the X inactivation process.
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X chromosome inactivation
is an important
form of epigenetic regulation
that evolved in mammals
to equalize the levels of expression
of genes on the X chromosome,
in XX females relative
to XY males.
Briefly,
during early development
of a female embryo,
each individual cell
triggers inactivation
of one of the two X chromosomes
that are present.
The process is normally random.
So in an individual cell,
there's an equal probability
of the X chromosome inherited
from the mother or the father
being selected
as the inactive X.
Once X inactivation
has occurred,
cells remember
which of the two X chromosomes
was inactivated through
all subsequent cell generations.
As a consequence,
female mammals or chimeras
comprised of a mosaic
or patchwork of cell populations
with either one
or the other X chromosome
being inactive.
A classical illustration
of X chromosome inactivation
is seen in the coat
of the calico cat,
which you can see in this image.
A gene that gives rise
to orange coat color
lies on the X chromosome.
And calico cats
are heterozygous
for this gene.
The wild type allele encodes
black coat color.
So when X inactivation occurs
in early development,
cells either
inactivate the chromosome
with the wild type gene,
giving rise
to orange coat color,
or the chromosome
with the orange gene,
giving rise to black coat color.
These individual cells then
expand into a clonal patch cells
during further development,
giving rise to these areas
with either orange
or black coat color.
1:42
X chromosome
inactivation results
in the transcriptional
silencing of genes
located on that chromosome.
The underlying basis
for this process
is a change
in the state of chromatin,
referring to DNA
and its associated histone
and non-histone proteins.
In simplified terms,
chromatin can exist
either in an open conformation,
termed U-chromatin,
or a compacted conformation,
termed heterochromatin.
The inactive X is an example
of the latter.
This point is illustrated
in the image
of an interphase nucleus
from a female somatic cell,
stained with DAPI,
a blue-fluorescent dye
that binds the DNA.
The intense DAPI focus,
indicated with the arrow,
is the compacted heterochromatic
inactive X chromosome.
This structure
was first observed
by Barr and Bertram in 1953
and is sometimes referred
to as "The Barr body".
