we combined the dynamic regulation of transcriptional activator binding, histone regulator inhibitors, and single-cell quantification of chromatin accessibility, mRNA, and protein to probe putative mechanisms.

Fluctuation ('noise') in gene expression is critical for mammalian cellular processes. Numerous mechanisms contribute to the origins of gene expression noise, yet large noises induced by single transcriptional activator species remain to be understood. Here, we combined the dynamic regulation of transcriptional activator binding, histone regulator inhibitors, and single-cell quantification of chromatin accessibility, mRNA, and protein to probe putative mechanisms. Using a light-induced expression system as our model, we show that the transcriptional activator forms a positive feedback loop with histone acetyltransferases CBP/p300. It generates epigenetic bistability in H3K27ac, which contributes to large gene expression noise. We showed that the gene expression noise was reduced by pulse-wide modulation of transcriptional activator binding activity due to alternating the system between high and low monostable states. Our findings could provide a mechanism-based approach to modulate noise in synthetic and endogenous expression systems.