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A model of spatially restricted transcription in opposing gradients of activators and repressors.

White MA, Parker DS, Barolo S, Cohen BA - Mol. Syst. Biol. (2012)

Bottom Line: This model quantitatively predicts the boundaries of gene expression within OARGs.When trained on experimental data, our model accounts for the counterintuitive observation that increasing the affinity of binding sites in enhancers of Hedgehog target genes produces more restricted transcription within Hedgehog gradients in Drosophila.Because our model is general, it may explain the role of low-affinity binding sites in many contexts, including mammalian Hedgehog gradients.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, MO 63108, USA.

ABSTRACT
Morphogens control patterns of transcription in development, often by establishing concentration gradients of a single transcriptional activator. However, many morphogens, including Hedgehog, create opposing activator and repressor gradients (OARGs). In contrast to single activator gradients, it is not well understood how OARGs control transcriptional patterns. We present a general thermodynamic model that explains how spatial patterns of gene expression are established within OARGs. The model predicts that differences in enhancer binding site affinities for morphogen-responsive transcription factors (TFs) produce discrete transcriptional boundaries, but only when either activators or repressors bind cooperatively. This model quantitatively predicts the boundaries of gene expression within OARGs. When trained on experimental data, our model accounts for the counterintuitive observation that increasing the affinity of binding sites in enhancers of Hedgehog target genes produces more restricted transcription within Hedgehog gradients in Drosophila. Because our model is general, it may explain the role of low-affinity binding sites in many contexts, including mammalian Hedgehog gradients.

Show MeSH
Morphogen gradients establish single activator gradients or opposing gradients of activators and repressors (OARGs). (A) A single transcriptional activator gradient. Activators occupy target enhancers in proportion to their concentration within the gradient. (B) OARGs. In OARGs, activators and repressors compete for enhancer binding.
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f1: Morphogen gradients establish single activator gradients or opposing gradients of activators and repressors (OARGs). (A) A single transcriptional activator gradient. Activators occupy target enhancers in proportion to their concentration within the gradient. (B) OARGs. In OARGs, activators and repressors compete for enhancer binding.

Mentions: Gradients of morphogens convey spatial information in developing embryos by acting through morphogen-responsive transcription factors (TFs). Some morphogens generate a single gradient of transcriptional activator (Figure 1A), and different target genes respond to different levels of this transcriptional activator. The expression pattern of target genes in these single activator gradients is strongly influenced by the affinity of activator binding sites (reviewed in Ashe and Briscoe, 2006 and Rogers and Schier, 2011). The role of binding site affinity can be explained by an activator threshold model: high-affinity binding sites are bound at low concentrations of activator, and thus enable a gene to respond broadly within the activator gradient. Conversely, the expression of genes regulated by low-affinity sites is more restricted because they respond only to higher concentrations of activator. This has been demonstrated in a variety of systems by directly modulating binding site affinity (Driever et al, 1989; Jiang and Levine, 1993; Arnosti et al, 1996; Wharton et al, 2004; Rowan et al, 2010).


A model of spatially restricted transcription in opposing gradients of activators and repressors.

White MA, Parker DS, Barolo S, Cohen BA - Mol. Syst. Biol. (2012)

Morphogen gradients establish single activator gradients or opposing gradients of activators and repressors (OARGs). (A) A single transcriptional activator gradient. Activators occupy target enhancers in proportion to their concentration within the gradient. (B) OARGs. In OARGs, activators and repressors compete for enhancer binding.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472688&req=5

f1: Morphogen gradients establish single activator gradients or opposing gradients of activators and repressors (OARGs). (A) A single transcriptional activator gradient. Activators occupy target enhancers in proportion to their concentration within the gradient. (B) OARGs. In OARGs, activators and repressors compete for enhancer binding.
Mentions: Gradients of morphogens convey spatial information in developing embryos by acting through morphogen-responsive transcription factors (TFs). Some morphogens generate a single gradient of transcriptional activator (Figure 1A), and different target genes respond to different levels of this transcriptional activator. The expression pattern of target genes in these single activator gradients is strongly influenced by the affinity of activator binding sites (reviewed in Ashe and Briscoe, 2006 and Rogers and Schier, 2011). The role of binding site affinity can be explained by an activator threshold model: high-affinity binding sites are bound at low concentrations of activator, and thus enable a gene to respond broadly within the activator gradient. Conversely, the expression of genes regulated by low-affinity sites is more restricted because they respond only to higher concentrations of activator. This has been demonstrated in a variety of systems by directly modulating binding site affinity (Driever et al, 1989; Jiang and Levine, 1993; Arnosti et al, 1996; Wharton et al, 2004; Rowan et al, 2010).

Bottom Line: This model quantitatively predicts the boundaries of gene expression within OARGs.When trained on experimental data, our model accounts for the counterintuitive observation that increasing the affinity of binding sites in enhancers of Hedgehog target genes produces more restricted transcription within Hedgehog gradients in Drosophila.Because our model is general, it may explain the role of low-affinity binding sites in many contexts, including mammalian Hedgehog gradients.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, MO 63108, USA.

ABSTRACT
Morphogens control patterns of transcription in development, often by establishing concentration gradients of a single transcriptional activator. However, many morphogens, including Hedgehog, create opposing activator and repressor gradients (OARGs). In contrast to single activator gradients, it is not well understood how OARGs control transcriptional patterns. We present a general thermodynamic model that explains how spatial patterns of gene expression are established within OARGs. The model predicts that differences in enhancer binding site affinities for morphogen-responsive transcription factors (TFs) produce discrete transcriptional boundaries, but only when either activators or repressors bind cooperatively. This model quantitatively predicts the boundaries of gene expression within OARGs. When trained on experimental data, our model accounts for the counterintuitive observation that increasing the affinity of binding sites in enhancers of Hedgehog target genes produces more restricted transcription within Hedgehog gradients in Drosophila. Because our model is general, it may explain the role of low-affinity binding sites in many contexts, including mammalian Hedgehog gradients.

Show MeSH