  Gene regulation relies on the specificity of transcription factor (TF) - DNA
interactions. In equilibrium, limited specificity may lead to crosstalk: a
regulatory state in which a gene is either incorrectly activated due to
noncognate TF-DNA interactions or remains erroneously inactive. We present a
tractable biophysical model of global crosstalk, where many genes are
simultaneously regulated by many TFs. We show that in the simplest regulatory
scenario, a lower bound on crosstalk severity can be analytically derived
solely from the number of (co)regulated genes and a suitable parameter that
describes binding site similarity. Estimates show that crosstalk could present
a significant challenge for organisms with low-specificity TFs, such as
metazoans, unless they use appropriate regulation schemes. Strong cooperativity
substantially decreases crosstalk, while joint regulation by activators and
repressors, surprisingly, does not; moreover, certain microscopic details about
promoter architecture emerge as globally important determinants of crosstalk
strength. Our results suggest that crosstalk imposes a new type of global
constraint on the functioning and evolution of regulatory networks, which is
qualitatively distinct from the known constraints acting at the level of
individual gene regulatory elements.
