Nonlinear
response
s to signals
are
widespread
natural
phenomen
a
that
affect vari
ous
cellular processes.
Nonlinearity
can be
a desirable characteristic for engineering living
organisms
because it can lead to more switch
-
like responses,
similar to
those
underlying the wiring in
electronics.
Steeper
functions are described as
ultrasensit
ive
,
and can be applied in
synthetic biology
by using
various techniques
including
receptor
decoys, multiple
co
-
operative
binding sites,
and
sequential
positive
feedbacks
.
Here, we explore the inherent non
-
linearity of a biological signaling
system to iden
tify functions that can potentially be exploited using cell genome
engineering
.
For
this,
we
performed genome
-
wide
transcription profiling
to identify
genes with
ultrasensitive
response function
s
to
Hepatocyte Growth Factor (HGF)
.
We
identified
3,
527
genes
that react to increasing concentrations of
HGF
, in
Madin
-
Darby
canine kidney (MDCK) cells
,
grown as cysts
in 3D collagen cell culture
.
By fitting a
generic Hill function to the dose
-
response
s
of
these
genes we
obtained a
measure
of
the
ultrasensitivity
of
HGF
-
responsive
genes
, identifying a subset with higher
apparent
Hill coefficients (e.g.
MMP1, TIMP1
,
SNORD75, SNORD86 and
ERRFI1
).
The regulatory regions of these genes are
potential
candidates for
future
engineering
of
synthetic mammalian gene ci
rcuits r
equiring non
linear responses to HGF
signalling.