Noise–mean relationship in mutated promoters

Abstract

Gene expression depends on the frequency of transcription events (burst frequency) and on the number of mRNA molecules made per event (burst size). Both processes are encoded in promoter sequence, yet their dependence on mutations is poorly understood. Theory suggests that burst size and frequency can be distinguished by monitoring the stochastic variation (noise) in gene expression: Increasing burst size will increase mean expression without changing noise, while increasing burst frequency will increase mean expression and decrease noise. To reveal principles by which promoter sequence regulates burst size and frequency, we randomly mutated 22 yeast promoters chosen to span a range of expression and noise levels, generating libraries of hundreds of sequence variants. In each library, mean expression (m) and noise (coefficient of variation, h) varied together, defining a scaling curve: h 2 = b/m + h ext 2 . This relation is expected if sequence mutations modulate burst frequency primarily. The estimated burst size (b) differed between promoters, being higher in promoter containing a TATA box and lacking a nucleosome-free region. The rare variants that significantly decreased b were explained by mutations in TATA, or by an insertion of an out-of-frame translation start site. The decrease in burst size due to mutations in TATA was promoter-dependent, but independent of other mutations. These TATA box mutations also modulated the responsiveness of gene expression to changing conditions. Our results suggest that burst size is a promoter-specific property that is relatively robust to sequence mutations but is strongly dependent on the interaction between the TATA box and promoter nucleosomes.

Clk post-transcriptional control denoises circadian transcription both temporally and spatially

“…As stated above, the levels of CLK per cell are similar in ClkWT and ClkSV40 flies; however, due to the strong post-transcriptional regulation provided by the Clk 3 0 UTR, the same levels of protein are achieved by much lower transcriptional activity of the Clk promoter in ClkSV40 flies. In agreement with the established inverse relationship between transcriptional levels and noise [52][53][54][55] , our model predicted that in ClkSV40 flies CLK-driven activity would be more sensitive to transcriptional noise and hence more variable. Clk is involved in the development of the circadian neurons as well as in the control of accurate circadian transcription.…”

Noise in gene expression is coupled to growth rate

“…This high variability of the condition-specific genes coincides with their promoter architectures, which are generally highly occupied by nucleosomes, remodeled by the SAGA complex, and contain strong TATA elements ( Fig. 4A; Newman et al 2006;Field et al 2008;Tirosh and Barkai 2008;Zenklusen et al 2008;Hornung et al 2012). As these features are encoded mainly by the promoter sequence, we verified that these features are also strongly correlated with expression variability in our library in fast growth conditions (Supplemental Fig.…”

What have single-molecule studies taught us about gene expression?

“…In eukaryotes, bursting behavior has been observed to vary widely and be more gene-specific. In yeast, promoter sequences have been shown to have a strong effect on bursting behavior (Hornung et al 2012), and mutations in the TATA box could change burst size (Blake et al 2006). These results reinforce the connection to earlier work on transcription reinitiation (Hawley and Roeder 1987;Yudkovsky et al 2000), although it is not yet clear that these phenomena are the same in vivo.…”