Graded versus ON/OFF control in quantitative gene expression and epigenetic memory

How can expression of a specific gene be quantitatively regulated? In this review, we discuss two possible modalities. In one, the level of mRNA generated from each gene copy can be smoothly varied giving graded analogue control. In a second, some gene copies generate high mRNA levels whilst others generate very low levels, giving ON/OFF digital control, with the fraction of copies with high or low expression being regulated. We focus on why in different contexts one modality would be preferred over the other, how these two modalities can be generated through transcriptional regulation, and discuss whether ON/OFF control is particularly linked to epigenetic memory. We argue that digital control arises for memory mediated by trans-factor feedback loops and histone modifications, but not necessarily for DNA methylation. We also examine how these expression modes can be established at one specific target, Arabidopsis FLOWERING LOCUS C (FLC). Graded expression and switching to ON/OFF control occur during early development and during long-term cold exposure and both are key to FLC regulation.