Transcriptional Regulation
Example regulatory circuits
Simple negative feedback – homeostasis
Toggle switch – choice and commitment
Cycle – alternation of multiple states
Simple negative feedback
An activity leads to inhibition of said activity
Gene produces activator that activates promotor of repressor which activates
promotor that stops the activator – maintains balance
Steady state created
External influence can change balance
Chaperone proteins assist in folding of proteins
A stress can cause an unfolding protein response
Chaperone recognises protein with hydrophobic surfaces facing outwards
Chaperones bind to correct unfolding
Hsp70 normally binds to Hsf1 transcription factor
which keeps Hsp70 inactive as the transcription
factor cannot bind to activation site
In presence of unfolded protein, transcription
factor releases Hsp70
More Hsf1 which activates the gene to produce
Hsp70
Once the cell is oversaturated with Hsp70, it
begins to bind to Hsf1 again which reduces the
production of Hsp70 bringing the ratio back to
balanced
In healthy neurones, HSF1 is important in
multiple proteins which are for cell survival and
maintenance
In certain diseases, unfolded protein responses
can be mimicked so the system cannot return
to equilibrium
Huntington's disease, develops sequences that
act on proteins which are important for HSF1 –
capacity to deal with stress responses is reduced
Toggle switch circuit
Two possible mutually exclusive outcomes
Two genes each encode proteins that enhance the
function of the gene but reduce the function of the other
gene
Whichever gene gains advantage will have the function
amplified
If b inhibits c and c inhibits b, if you have more b then c is
inhibited, and more b is produced or vice versa
Two steady states the system can be in
Bacteriophage lambda – can lysogeny (co-existence) or lysis (murder) the cell
, The bacteriophage can stay in the cell and merge DNA and the switch to lysis state
and releases bacteriophages killing the cell
Both advantages in certain scenarios – if lots of host bacteria cells available then lysis
more effective, however, if fewer host cells available then lysogeny is more effective
Bidirectional promoter (lambda switch region) – transcription proceeds via Prm
(producing C1) or Pr region (producing cro)
If cro is produced then a homeodimer of 2
cro which promotes expression of cro and
inhibits the expression of c1
If c1 produced a homeodimer of c1 promotes
the expression of c1 and inhibition of cro
Both act on PL promotor locus, if more cro
then C3 inhibited, if more c1 then c3
expressed
C3 degradation reaction inhibits c2
degradation
Cro produces C2 and C2 activates a promotor
that is in the same orientation as C1
However, C2 is unstable so does not affect reaction unless C3 is present to stabilise it
Cro promotes lysis state and c1 promotes lysogeny state
Whichever produces more, in the beginning, gains the switch and maintains
production
Cycles of transcription
Data encoded using biological cycles
Repressilator – 3 bacterial repressors which
each activator by repressor sensitive
promotors
If one repressor is made then promotor of
another repressor is activated, which in turn
activates the promotor of the next repressor
forming a cycle as each is toggled on and off
Real examples of transcriptional cycles
Somitogenesis
Circadian clock
Cell cycle
Properties of Somitogenesis Oscillator
Rhythm in Presomitic mesoderm (PSM) cells
Fixed number of cycles
Rhythm across cells
Fixed periodicity – 6 hours humans, 2 hours mouse, 30 min zebrafish
Somites emerge from tail end
Clock and wavefront model – assumes there is a gradient and a clock periodic signal
– slower level of oscillation causes slower bigger fewer somites, increased speed of
oscillation causes smaller and more somites
Hes6 mutant in zebrafish causes slower somite clock oscillation and hence fewer
somites form
Her1 marks somites
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