Intrinsic Limits to Gene Regulation by Global Crosstalk

Gene activity is mediated by the specificity of binding interactions between special proteins, called transcription factors, and short regulatory sequences on the DNA, where different protein species preferentially bind different DNA targets. Limited interaction specificity may lead to crosstalk: a regulatory state in which a gene is either incorrectly activated due to spurious interactions or remains erroneously inactive. Since each protein can potentially interact with numerous DNA targets, crosstalk is inherently a many-protein many-target problem, yet has previously only been studied in a reduced single-protein setting. I construct a theoretical framework to analyze the global crosstalk and obtain a “crosstalk floor” that cannot be overcome. I find that crosstalk in regulatory interactions puts fundamental limits on the reliability of gene regulation that are not easily mitigated by tuning proteins concentrations or by complex regulatory schemes proposed in the literature. My results suggest that crosstalk imposes a previously unexplored global constraint on the functioning and the maximal size of such networks, which is qualitatively distinct from the known constraints that act at the level of the individual gene. I discuss this problem in the broader context of combinatorial explosion of configurations in self-assembled systems.