  Models of transcriptional regulation that assume equilibrium binding of
transcription factors have been very successful at predicting gene expression
from sequence in bacteria. However, analogous equilibrium models do not perform
as well in eukaryotes, most likely due to the largely out-of-equilibrium nature
of eukaryotic regulatory processes. These processes come with unavoidable
energy expenditure at the molecular level to support precise, reliable, or fast
gene expression responses that could correspond to evolutionarily optimized
regulatory strategies. Unfortunately, the space of possible non-equilibrium
mechanisms is vast and predominantly uninteresting. The key question is
therefore how this space can be navigated efficiently, to focus on mechanisms
and models that are biologically relevant. In this review, we advocate for the
normative role of theory - theory that prescribes rather than just describes -
in providing such a focus. Theory should expand its remit beyond inferring
models from data (by fitting), towards identifying non-equilibrium gene
regulatory schemes (by optimizing) that may have been evolutionarily selected
due to their favorable functional characteristics which outperform regulation
at equilibrium. This approach can help us navigate the expanding complexity of
regulatory architectures, and refocus the questions about the observed
biological mechanisms from how they work towards why they have evolved in the
first place. We illustrate our reasoning by toy examples for which we provide
simulation code.
