Quantitative control of noise in mammalian gene expression by dynamic histone regulation
Deng Tan,
Rui Chen,
Yuejian Mo,
Shu Gu,
Jiao Ma,
Wei Xu,
Xibin Lu,
Huiyu He,
Fan Jiang,
Weimin Fan,
Yili Wang,
Xi Chen,
Wei Huang
Affiliations
Deng Tan
School of Life Sciences, Southern University of Science and Technology, Shenzhen, China; Department of Chemistry, The Hong Kong University of Science and Technology, Kowloon, Hong Kong, China
Rui Chen
School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
Yuejian Mo
School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
Shu Gu
School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
Jiao Ma
School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
Wei Xu
Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
Xibin Lu
Core Research Facilities, Southern University of Science and Technology, Shenzhen, China
Huiyu He
School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
Fan Jiang
Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, China
Weimin Fan
School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
Yili Wang
Core Research Facilities, Southern University of Science and Technology, Shenzhen, China
Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
Fluctuation ('noise') in gene expression is critical for mammalian cellular processes. Numerous mechanisms contribute to its origins, yet the mechanisms behind large fluctuations that are induced by single transcriptional activators remain elusive. Here, we probed putative mechanisms by studying the dynamic regulation of transcriptional activator binding, histone regulator inhibitors, chromatin accessibility, and levels of mRNAs and proteins in single cells. Using a light-induced expression system, we showed that the transcriptional activator could form an interplay with dual functional co-activator/histone acetyltransferases CBP/p300. This interplay resulted in substantial heterogeneity in H3K27ac, chromatin accessibility, and transcription. Simultaneous attenuation of CBP/p300 and HDAC4/5 reduced heterogeneity in the expression of endogenous genes, suggesting that this mechanism is universal. We further found that the noise was reduced by pulse-wide modulation of transcriptional activator binding possibly as a result of alternating the epigenetic states. Our findings suggest a mechanism for the modulation of noise in synthetic and endogenous gene expression systems.
