Transcriptional coupling of neighboring genes and gene expression noise: evidence that gene orientation and noncoding transcripts are modulators of noise

Abstract

How is noise in gene expression modulated? Do mechanisms of noise control impact genome organization? In yeast, the expression of one gene can affect that of a very close neighbor. As the effect is highly regionalized, we hypothesize that genes in different orientations will have differing degrees of coupled expression and, in turn, different noise levels. Divergently organized gene pairs, in particular those with bidirectional promoters, have close promoters, maximizing the likelihood that expression of one gene affects the neighbor. With more distant promoters, the same is less likely to hold for gene pairs in nondivergent orientation. Stochastic models suggest that coupled chromatin dynamics will typically result in low abundance-corrected noise (ACN). Transcription of noncoding RNA (ncRNA) from a bidirectional promoter, we thus hypothesize to be a noise-reduction, expression-priming, mechanism. The hypothesis correctly predicts that protein-coding genes with a bidirectional promoter, including those with a ncRNA partner, have lower ACN than other genes and divergent gene pairs uniquely have correlated ACN. Moreover, as predicted, ACN increases with the distance between promoters. The model also correctly predicts ncRNA transcripts to be often divergently transcribed from genes that a priori would be under selection for low noise (essential genes, protein complex genes) and that the latter genes should commonly reside in divergent orientation. Likewise, that genes with bidirectional promoters are rare subtelomerically, cluster together, and are enriched in essential gene clusters is expected and observed. We conclude that gene orientation and transcription of ncRNAs are candidate modulators of noise.

FIG. 1.—

A simplified representation of the effect of bipromoter architecture on expression priming and noise. Consider a bipromoter architecture (A) or unidirectional architecture (B). With the bipromoter architecture, a transcript (red, with red TF and red gene) is made (stage 1). This keeps the chromatin open so that should the TF (black circle) for the gene on the opposite strand (black) become available transcription can occur (stage 2). This in turn makes it more likely that a TF for the red gene can have access should it appear (stage 3). This predisposes to avoidance of randomly spaced (in time) transcriptional bursting. Moreover, constant expression, for example, of a small ncRNA (red) (repetition of stage 1 or polymerase pausing) will prime the focal gene (black) for expression when expression is needed, assuming no interference between the two sets of TFs. By contrast, with unidirectional promoters (B), the promoter can be trapped in closed chromatin (shown as parentheses). When the relevant TF appears (stage 2) expression is hence not possible but instead must wait for the chromatin to open (stage 3). With random shutting of chromatin after expression (return to stage 1), bursting of gene expression is expected and hence typically high noise.

FIG. 2.—

The relationship between the independence between two neighboring genes and various noise and coexpression parameters for nine values of p_c (the probability of chromatin closing if open) and p_o (the probability of chromatin opening if closed) in simulations under the mixed model. Data: transcriptional noise, blue; protein noise, red; strength of protein noise, orange; coexpression, green; chromatin fluctuation, black; proportion of time chromatin open, gray. Other parameter values: N = 100, p_t = 0.9, p_d = 0.7. Noise strength is normalized to the highest value in any given plot so that the maximum value is unity.

FIG. 3.—

Genes that share a promoter (5′ NFR) with either a noncoding transcript or coding transcript (ORF) show lower abundance-corrected expression noise than genes without any bipromoter transcript. Number of genes that have noise value in each category: With noncoding: 216; with ORF: 537; other (genes that do not share 5′ NFR with other transcripts): 1,072. Box width indicates sample sizes. For the distribution of the data, see supplementary figure 8 (Supplementary Material online).

FIG. 4.—

The relationship between the distance between TSSs and the mean noise level of the two genes as a function of gene orientation: (A) Divergent, (B) Cooriented, (C) Convergent. In each case, the data are split into bins with equal numbers in each bin, for a given orientation. Error bars indicate standard error of the mean. Only for the divergent genes is there a significant correlation between distance and noise.