Chromatin enables precise and scalable gene regulation with factors of limited specificity.

Biophysical constraints limit the specificity with which transcription factors (TFs) can target regulatory DNA. While individual nontarget binding events may be low affinity, the sheer number of such interactions could present a challenge for gene regulation by degrading its precision or possibly leading to an erroneous induction state. Chromatin can prevent nontarget binding by rendering DNA physically inaccessible to TFs, at the cost of energy-consuming remodeling orchestrated by pioneer factors (PFs). Under what conditions and by how much can chromatin reduce regulatory errors on a global scale? We use a theoretical approach to compare two scenarios for gene regulation: one that relies on TF binding to free DNA alone and one that uses a combination of TFs and chromatin-regulating PFs to achieve desired gene expression patterns. We find, first, that chromatin effectively silences groups of genes that should be simultaneously OFF, thereby allowing more accurate graded control of expression for the remaining ON genes. Second, chromatin buffers the deleterious consequences of nontarget binding as the number of OFF genes grows, permitting a substantial expansion in regulatory complexity. Third, chromatin-based regulation productively co-opts nontarget TF binding for ON genes in order to establish a "leaky" baseline expression level, which targeted activator or repressor binding subsequently up- or down-modulates. Thus, on a global scale, using chromatin simultaneously alleviates pressure for high specificity of regulatory interactions and enables an increase in genome size with minimal impact on global expression error.