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2017 ; 27
(1
): 87-94
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Large-scale mapping of gene regulatory logic reveals context-dependent repression
by transcriptional activators
#MMPMID27965290
van Dijk D
; Sharon E
; Lotan-Pompan M
; Weinberger A
; Segal E
; Carey LB
Genome Res
2017[Jan]; 27
(1
): 87-94
PMID27965290
show ga
Transcription factors (TFs) are key mediators that propagate extracellular and
intracellular signals through to changes in gene expression profiles. However,
the rules by which promoters decode the amount of active TF into target gene
expression are not well understood. To determine the mapping between promoter DNA
sequence, TF concentration, and gene expression output, we have conducted in
budding yeast a large-scale measurement of the activity of thousands of designed
promoters at six different levels of TF. We observe that maximum promoter
activity is determined by TF concentration and not by the number of binding
sites. Surprisingly, the addition of an activator site often reduces expression.
A thermodynamic model that incorporates competition between neighboring binding
sites for a local pool of TF molecules explains this behavior and accurately
predicts both absolute expression and the amount by which addition of a site
increases or reduces expression. Taken together, our findings support a model in
which neighboring binding sites interact competitively when TF is limiting but
otherwise act additively.