 Transcriptional Regulation: Effects of Promoter Proximal Pausing on Speed, Synchrony and ReliabilityAlistair N Boettiger, Peter L Ralph and Steven N Evans PLOS Computational Biology, 2011, vol. 7, issue 5, 1-14 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.Author Summary: Gene activation is an inherently random process because numerous diffusing proteins and DNA must first interact by random association before transcription can begin. 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. For these genes, activation merely releases polymerase from the preassembled complex to transcribe the gene. It has been proposed on the basis of experiments that such a mechanism, while possibly costly, increases both the speed and the synchrony of the process of gene transcription. We study a realistic model of gene transcription, and show that this conclusion holds for all but a tiny fraction of the space of physical rate parameters that govern the process. 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. Our approach has also generated tools with which one can study the effects of analogous changes in other molecular networks and determine the relative importance of various molecular binding rates to particular system properties. Date: 2011 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1001136 DOI: 10.1371/journal.pcbi.1001136 Access Statistics for this article More articles in PLOS Computational Biology from Public Library of Science |
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