Abstract
Recent whole genome polymerase binding assays in the Drosophila embryo have shown that a substantial proportion of uninduced genes have pre-assembled RNA polymerase-II transcription initiation complex (PIC) bound to their promoters. These constitute a subset of promoter proximally paused genes for which mRNA elongation instead of promoter access is regulated. This difference can be described as a rearrangement of the regulatory topology to control the downstream transcriptional process of elongation rather than the upstream transcriptional initiation event. It has been shown experimentally that genes with the former mode of regulation tend to induce faster and more synchronously, and that promoter-proximal pausing is observed mainly in metazoans, in accord with a posited impact on synchrony. However, it has not been shown whether or not it is the change in the regulated step per se that is causal. We investigate this question by proposing and analyzing a continuous-time Markov chain model of PIC assembly regulated at one of two steps: initial polymerase association with DNA, or release from a paused, transcribing state. Our analysis demonstrates that, over a wide range of physical parameters, increased speed and synchrony are functional consequences of elongation control. Further, we make new predictions about the effect of elongation regulation on the consistent control of total transcript number between cells. We also identify which elements in the transcription induction pathway are most sensitive to molecular noise and thus possibly the most evolutionarily constrained. Our methods produce symbolic expressions for quantities of interest with reasonable computational effort and they can be used to explore the interplay between interaction topology and molecular noise in a broader class of biochemical networks. We provide general-purpose code implementing these methods.
Highlights
Investigations in yeast [1,2] led to the hypothesis that in most organisms the recruitment of polymerase to the promoter is the primary regulated step in the activation of gene expression [3,4,5,6]
For many genes the necessary protein–DNA associations only begin after activation, but it has recently been noted that a large class of genes in multicellular organisms can assemble the initiation complex of proteins on the core promoter prior to activation
The improved control of cell-to-cell variations afforded by regulation through a paused polymerase may help multicellular organisms achieve the high degree of coordination required for development
Summary
Investigations in yeast [1,2] led to the hypothesis that in most organisms the recruitment of polymerase to the promoter is the primary regulated step in the activation of gene expression [3,4,5,6]. Zeitlinger et al [7] generated tissue-specific whole-genome polymerase binding data in Drosophila melanogaster and showed that regulation of polymerase release from the promoter is widespread during development Their data shows that some 15% of tissue-specific genes bind polymerase to their promoters in all tissues, even though each gene only allows polymerase to proceed through the coding sequence in a specific tissue (see Figure S1). Differential expression of these genes is made possible by a paused state wherein a polymerase remains stably bound but precisely stopped a short distance from the promoter and awaits a regulated release that is only triggered in the appropriate tissue [7]. Many metazoa have been shown to have, genome-wide, disproportionate amounts of polymerase bound at promoter regions as compared to coding regions [7,8,10,11]
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