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Eukaryotic Gene Expression: - Bacterial Genes Have A Ground State That Permits Transcription
Eukaryotic Gene Expression: - Bacterial Genes Have A Ground State That Permits Transcription
proteins
Regulatory 1. Inhibition of initiation factors
through phosphorylation
mechanisms of – eIF phosphorylation inhibits its
function and can be reversed
translational through dephosphorylation
2. Inhibition of initiation factors
initiation by binding to specific factors
– Interference with eIF4E and eIF-
4G activity by 4E-BP’s.
3. Inhibition of specific mRNA
by binding of inhibitory
proteins to sequences in the
3’untranslated region
Phosphorylation of • Maturation of red blood
cells involves a stage in
eIF-2 inhibits its which reticulocytes translate
mRNA left behind after the
activity loss of the nucleus
• Reticulocytes regulate the
amount of globin
synthesized by
phosphorylating eIF-2
– When there is heme
deficiency globin synthesis is
wasteful since hemoglobin
cannot be synthesized
• Low heme activates HCI
which phosphorylates eIF-2
– Phosphorylated eIF2 binds
eIF2 binding protein and is
unavailable for translational
initiation
eIF4E inhibition
• eIF4E is necessary to bind
the 5’ CAP in order to from
an initiation complex for
translation
– Normally it binds eIF4G
• Maskin binds eIF4E
(preventing it from binding
eIF4G) when it is bound to
an mRNA through
interaction with CEPB
Developmental control • The study of fruit fly
development resulted in
of gene expression the discovery of a number
of genes involved in
human disease
– Although fruit fly
development is greatly
different in the processes
leading to the final form,
the activation of genes and
the structure of gene
products and their
participation in the
formation of patterns and
structures have parallels in
human gene regulation and
the structure of human
regulatory gene products
Fly development is controlled by
gene expression
• The conceptually difficult part of this is to
understand how a single cell can create multiple,
morphologically different structures starting from
a seemingly symmetrical, undifferentiated state
merely by dividing.
• It is easier to think of the process in parts and then
add up the whole than to see a cell turn into a fly
and attempt to understand the entire process at
once
• Maternal genes
– Made by the female and
Three gene families exist within the egg at
the time of fertilization
are responsible for • Responsible for
establishing the polarity of
early development the early embryo
• Zygotically acting genes
– Segmentation genes
• These establish a
repeating pattern of body
segments
– Homeotic genes
• These establish the
identity of the segments
• This is a distinction in
structure established
Polarity between two poles.
– The distinction needn’t be
great, only a morphological
difference is enough to
create polarity
– Without polarity, further
structures would have no
way of organizing
themselves
• Segments would be
repeating structures that
are all the same
– Establishing polarity is thus
the earliest developmental
event
• Polarity is actually
established by the
assymetry of the egg
• This yields pole cells on
one end of the zygote
• This is obvious in the formation
of the fly abdomen
– Repeating abdominal segments are
Segmentation very similar in appearance
– However this patterning extends
from end to end of the fly
• The patterns are given different
identities by homeotic genes
• Thus the head and abdomen begin
as segments similar to abdominal
segments
– But polarity makes them
different, and therefore the genes
that are expressed within each
segment differs
– Segments are created and further
divided into smaller segments
• Gap genes create the largest
segments
• Pair rule and segment polarity
genes subdivide the largest
segments
• These give rise to the dramatic
mutants of Drosophila
• Once segments are established with
the proper polarity, homeotic genes
create unique structures
• Mutation of a particular homeotic
gene results in the formation of a
structure that is due to the action of
another homeotic gene
– The homeotic genes are controlled by
their position within a gradient of polarity
– So if one segment was destined to give
rise to antennae, but lacked the homeotic
gene due to mutation, it would create the
next most available structure
Homeotic genes
Antennaepedia • Antennaepedia represents the
mutation of a gene that
would create an antennae
– Antennapedia is a transcription
factor that coordinately
controls expression of genes,
that when expressed result in
an antennae
• In its absence, the next most
similar structure is a leg
– The normal leg is also formed
in the next segment
– The gene encoding the protein
controlling leg development is
expressed at lower
concentrations in the head
segment than antennapedia
gene, but in the absence of
antennapedia, it is the most
highly expressed protein
capable of activating genes
that result in a structure
• Maternal genes establish
Key genes are polarity due to formation of
gradients
expressed early – Front to back and top to bottom
gradients establish anterior
posterior and dorsal ventral
gradients
• When cells are formed in the
blastoderm, they form within an
environment in which the
concentration of transcription
factors will vary along one axis
– This varies the type and numbers
of genes that are expressed within
any cell
• To the left is bicoid RNA
(upper) and bicoid protein
(lower) in the early embryo
– The RNA gradient is present in the
egg and establishes the protein
gradient
• Bicoid is a maternal gene that
A few examples of controls expression of
segmentation genes
developmental – It is a transcription factor that
activates segmentation genes
genes – And a translational repressor
• It appears in the anterior of an egg,
and its concentration falls of
towards the posterior
• The gradient is maintained during
formation of the larvae
• Experiments with bcd mutants
– (a) A failure of bicoid to be expressed
means a fly develops with two
posteriors rather than an anterior and a
posterior
– (b)injecting cytoplasm from a normal
embryo rescues the embryo (makes an
anterior)
– ( c) injecting bicoid mRNA also
rescues
• It represses translation of caudal
in the anterior of the fly larvae
– Caudal is a transcription factor
What bicoid does found uniformly throughout the
larvae, and it creates the posterior
end
• And activates expression of
hunchback
– Hunchback is a transcription factor
that creates the anterior end
• The bicoid gradient means it has
these effects only in the anterior
end
• Without bicoid, caudal is not
repressed in the anterior end and
hunchback is not transcribed
Nanos
• This is a translational
repressor that is found at
highest concentrations in the
posteror of a fly larvae
• It acts in concert with the
uniformly distributed
pumilio gene product to
translationally repress
hunchback
• This results in establishment
of high caudal gene product
and inactivated hunchback
mRNA, meaning the
posteriorizing effect of
caudal dominates
Some Gap genes
• Gap genes create a gross
form of segmentation in
the early embryo
• They are overlayed onto
the pair-rule gene
expression to create
complex transcriptional
signals
• These are the expression
patterns of the hb-z, Kr
and kni genes
• These are two segmentation
fushi tarazu genes known as pair rule genes
that split a segment in two
and eve – Ftz establishes the “pair rule”
• Two segments form out of one
• Without it the fly forms 7 rather
than 14 segments
• Ftz (blue) is expressed in each
segment, in the anterior half of
the segment
– This expression pattern is again the
result of the action of an anterior
posterior gradient, but now within
each segment
• Eve (brown) for even-skipped
are expressed in the posterior
half of each segment
• Both ftz and eve are
homeodomain transcription
factors that control expression of
genes expressed in the segments