Cis -regulatory control of transcriptional timing and noise in response to estrogen.

Cis-Regulatory Elements (CREs) control transcription levels, temporal dynamics, and cell-cell variation - often referred to as transcriptional noise. However, the combination of regulatory proteins and epigenetic features necessary to control different transcription attributes is not fully understood. Here, single-cell RNA-seq (scRNA-seq) is conducted during a time course of estrogen treatment to identify genomic predictors of expression timing and noise. We find that genes associated with multiple active enhancers exhibit faster temporal responses. Synthetic modulation of enhancer activity verifies that activating enhancers accelerates expression responses, while inhibiting enhancers results in a more gradual response. Noise is controlled by a balance of promoter and enhancer activity. Active promoters are found at genes with low noise levels, whereas active enhancers are associated with high noise. Finally, we observe that co-expression across single cells is an emergent property associated with chromatin looping, timing, and noise levels. Overall, our results indicate a fundamental tradeoff between a gene’s ability to quickly respond to incoming signals and maintain low variation across cells.