RT Journal Article
SR Electronic
T1 Quantitative Control of Noise in Mammalian Gene Expression by Dynamic Histone Regulations
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.12.20.423693
DO 10.1101/2020.12.20.423693
A1 Deng Tan
A1 Rui Chen
A1 Yuejian Mo
A1 Wei Xu
A1 Xibin Lu
A1 Huiyu He
A1 Shu Gu
A1 Fan Jiang
A1 Weimin Fan
A1 Yilin Wang
A1 Xi Chen
A1 Wei Huang
YR 2020
UL http://biorxiv.org/content/early/2020/12/21/2020.12.20.423693.abstract
AB Fluctuation (‘noise’) in gene expression is critical for mammalian cellular processes. Numerous mechanisms contribute to its origins, yet large noises induced by single transcriptional activator species remain to be experimentally 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, 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 noise. Disable of the positive feedback loop by CBP/p300 and HDAC4/5 inhibitors also reduces heterogeneity in endogenous genes, suggesting a universal mechanism. We showed that the noise was reduced by pulse-wide modulation of transcriptional activator binding 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 gene expressions.