 Gene Expression Noise in Spatial Patterning: hunchback Promoter Structure Affects Noise Amplitude and Distribution in Drosophila SegmentationDavid M Holloway, Francisco J P Lopes, Luciano da Fontoura Costa, Bruno A N Travençolo, Nina Golyandina, Konstantin Usevich and Alexander V Spirov PLOS Computational Biology, 2011, vol. 7, issue 2, 1-18 Abstract: Positional information in developing embryos is specified by spatial gradients of transcriptional regulators. One of the classic systems for studying this is the activation of the hunchback (hb) gene in early fruit fly (Drosophila) segmentation by the maternally-derived gradient of the Bicoid (Bcd) protein. Gene regulation is subject to intrinsic noise which can produce variable expression. This variability must be constrained in the highly reproducible and coordinated events of development. We identify means by which noise is controlled during gene expression by characterizing the dependence of hb mRNA and protein output noise on hb promoter structure and transcriptional dynamics. We use a stochastic model of the hb promoter in which the number and strength of Bcd and Hb (self-regulatory) binding sites can be varied. Model parameters are fit to data from WT embryos, the self-regulation mutant hb14F, and lacZ reporter constructs using different portions of the hb promoter. We have corroborated model noise predictions experimentally. The results indicate that WT (self-regulatory) Hb output noise is predominantly dependent on the transcription and translation dynamics of its own expression, rather than on Bcd fluctuations. The constructs and mutant, which lack self-regulation, indicate that the multiple Bcd binding sites in the hb promoter (and their strengths) also play a role in buffering noise. The model is robust to the variation in Bcd binding site number across a number of fly species. This study identifies particular ways in which promoter structure and regulatory dynamics reduce hb output noise. Insofar as many of these are common features of genes (e.g. multiple regulatory sites, cooperativity, self-feedback), the current results contribute to the general understanding of the reproducibility and determinacy of spatial patterning in early development.Author Summary: Noise is an intrinsic part of biochemical systems such as gene regulation networks. Noisy gene expression has been well documented in populations of single cells, and is likely a key mechanism in evolutionary change. But in developing embryos, cells within a tissue must overcome such variability in order to provide the uniformity required to coordinate multiple events. Reproducibility and determinacy of the spatial protein patterns preceding tissue differentiation is a critical aspect of development. In this study, we use anterior-posterior (AP) segmentation in the fruit fly (Drosophila) to understand how gene regulation dynamics control noise. One of the earliest AP patterning events is the anterior activation of the hunchback (hb) gene by the maternally-derived Bicoid (Bcd) protein gradient. This interaction has been very well characterized, providing the tools for us to develop a stochastic model of hb gene regulation to make predictions about expression noise, and to corroborate these experimentally. For hb, we show that self-regulation is a critical part of controlling noise, and the multiple Bcd binding sites in the hb promoter also enhance pattern reproducibility. To the degree that such features are shared by other genes, these noise-reducing mechanisms may be common to many pattern forming events. Date: 2011 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1001069 DOI: 10.1371/journal.pcbi.1001069 Access Statistics for this article More articles in PLOS Computational Biology from Public Library of Science |
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