NDLI: Gene expression noise in embryonic spatial patterning: Reliable formation of the head-to-tail axis in the fruit fly

Content Provider	IEEE Xplore Digital Library
Author	Holloway, D.M. Spirov, A.V.
Copyright Year	2011
Description	Author affiliation: Computer Science and CEWIT, State University of New York at Stony Brook, USA (Spirov, A.V.) \|\| Mathematics Department, British Columbia Institute of Technology, Burnaby, Canada (Holloway, D.M.)
Abstract	Fruit flies serve as a model for understanding the genetic regulation involved in specifying the complex body plans of higher animals. The head-to-tail (anterior-posterior) axis of the fly (Drosophila) is established in the first hours of development. Maternally supplied factors form concentration gradients which direct embryonic (zygotic) genes where to be activated to express proteins. These protein patterns specify the positions and cell types of the body's tissues. Recent research has shown, comparing between embryos, that the zygotic gene products are much more precisely positioned than the maternal gradients, indicating an embryonic error reduction mechanism. Within embryos, there is the additional aspect that DNA and mRNA operate at very low copy number, and the associated high relative noise has the potential to strongly affect protein expression patterns. In recent work, we have focused on the noise aspects of positional specification within individual embryos. We simulate activation of hunchback (hb), a primary target of the maternal Bicoid (Bcd) protein gradient, which forms an expression pattern dividing the embryo into anterior and posterior halves. We use a master equation approach to simulate the stochastic dynamics of hb regulation, using the known details of the hb promoter, the region of DNA responsible for transcribing hb mRNA. This includes the binding/unbinding of Bcd molecules at the promoter, hb transcription, subsequent translation to Hb protein, binding/unbinding of Hb at the promoter (self-regulation), and diffusion of the Bcd and Hb proteins. Model parameters were set by deterministically matching large scale pattern features for a series of experimental expression patterns: wild-type (WT) embryos; hb mutants lacking self-regulation; and constructs in which portions of the hb promoter were used to express a reporter gene (lacZ). The model was then solved stochastically to predict the noise output in these different experiments. In subsequent noise measurements we experimentally corroborated a number of the predictions. These include that mRNA is noisier than protein, and that Hb self-regulation reduces noise. Results indicate that WT (self-regulatory) Hb output noise is predominantly dependent on the transcription and translation dynamics of its own expression, and is uncorrelated with Bcd fluctuations. This contradicts prior work, which had assumed a complete dependence of Hb fluctuations on Bcd fluctuations. In the constructs and mutant, which lack self-regulation, we find that increasing the number and strength of Bcd binding sites (there are 6 in the core hb promoter) provides a rudimentary level of noise reduction. The model is robust to the various Bcd binding site numbers seen across different fly species. New directions in the project include incorporating a known inhibitor of hb, Krüppel, into the model to study its effect on the noise dynamics. Our study has identified particular ways in which hb output noise is controlled. Since these involve common modes of gene regulation (e.g. multiple regulatory sites, self-regulation), these results contribute to the general understanding of the reproducibility and determinacy of spatial patterning in early development.
Starting Page	495
Ending Page	498
File Size	423972
Page Count	4
File Format	PDF
ISBN	9781457701894
e-ISBN	9781457701924
DOI	10.1109/ICNF.2011.5994379
Language	English
Publisher	Institute of Electrical and Electronics Engineers, Inc. (IEEE)
Publisher Date	2011-06-12
Publisher Place	Canada
Access Restriction	Subscribed
Rights Holder	Institute of Electrical and Electronics Engineers, Inc. (IEEE)
Subject Keyword	Proteins Embryo RNA Transcription noise Noise DNA Drosophila Gene regulation Spatial pattern Gene expression Mathematical model Embryo development
Content Type	Text
Resource Type	Article

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