Negative autoregulation linearizes the dose response and
suppresses the heterogeneity
of gene expression
D. Nevozhay, R. Adams, K. Murphy, K. Josić and G. Balazsi
Although several recent
studies have focused on gene autoregulation, the effects of
negative feedback (NF) on gene expression are not fully understood. Our
purpose here
was to determine how the strength of NF regulation affects the
characteristics of
gene expression in yeast cells harboring chromosomally integrated
transcriptional cascades that consist of the yEGFP reporter controlled
by (i) the constitutively
expressed tetracycline repressor TetR or (ii) TetR repressing its own
expression.
Reporter gene expression in the cascade without feedback showed a steep
(sigmoidal)
dose–response and a wide, nearly bimodal yEGFP distribution, giving
rise to a noise peak at intermediate levels of induction. We developed
computational models that
reproduced the steep dose–response and the noise peak and predicted
that negative
autoregulation changes reporter expression from bimodal to unimodal and
transforms
the dose–response from sigmoidal to linear. Prompted by these
predictions,
we constructed a “linearizer” circuit by adding TetR autoregulation to
our original cascade and observed a massive (7-fold) reduction of noise
at intermediate induction
and linearization of dose–response before saturation. A simple
mathematical argument
explained these findings and indicated that linearization is highly
robust to
parameter variations. These findings have important implications for
gene expression
control in eukaryotic cells, including the design of synthetic
expression systems.
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