title: Gene expression noise in spatial patterning: hunchback promoter structure affects noise amplitude and distribution in Drosophila segmentation.
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 hb(14F), 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.
authors.affiliation: Mathematics Department, British Columbia Institute of Technology, Burnaby, British Columbia, Canada. David_Holloway@bcit.ca
authors.forename: David M
authors.initials: DM
authors.lastname: Holloway
authors.forename: Francisco J P
authors.initials: FJ
authors.lastname: Lopes
authors.forename: Luciano
authors.initials: L
authors.lastname: da Fontoura Costa
authors.forename: Bruno A N
authors.initials: BA
authors.lastname: Travençolo
authors.forename: Nina
authors.initials: N
authors.lastname: Golyandina
authors.forename: Konstantin
authors.initials: K
authors.lastname: Usevich
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Spirov
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001665:Binding Sites / Q000235:genetics; D019521:Body Patterning / Q000235:genetics / Q000502:physiology; D019295:Computational Biology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000196:embryology* / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000706:statistics & numerical data; D018507:Gene Expression Regulation, Developmental; D017344:Genes, Insect; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008957:Models, Genetic; D009154:Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013269:Stochastic Processes; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; C056478:bcd protein, Drosophila; C061245:hb protein, Drosophila