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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.

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Repressor cooperativity establishes a middle gradient zone in which distinct gene expression boundaries are possible. (A) Hh gradient and the corresponding Gli OARG. [A] and [R] range from 0 to 100 in arbitrary units, with fraction activator and repressor shown on the scale. Dashed lines indicate the boundaries of the middle gradient zone, as defined by Equations (6) and (7). (B) Under a cooperative model (ω=30), different enhancer affinities define distinct boundaries of gene activation. As enhancer affinity increases (as K increases), the region of gene activation is more restricted. (C) Under a non-cooperative model there is no middle zone in which multiple gene expression boundaries are possible, and all genes are activated when [A]>[R], regardless of affinity.
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f2: Repressor cooperativity establishes a middle gradient zone in which distinct gene expression boundaries are possible. (A) Hh gradient and the corresponding Gli OARG. [A] and [R] range from 0 to 100 in arbitrary units, with fraction activator and repressor shown on the scale. Dashed lines indicate the boundaries of the middle gradient zone, as defined by Equations (6) and (7). (B) Under a cooperative model (ω=30), different enhancer affinities define distinct boundaries of gene activation. As enhancer affinity increases (as K increases), the region of gene activation is more restricted. (C) Under a non-cooperative model there is no middle zone in which multiple gene expression boundaries are possible, and all genes are activated when [A]>[R], regardless of affinity.

Mentions: Equations (6) and (7) define the boundaries of a middle zone of the OARG in which differences in enhancer TF binding site affinity will produce different boundaries of gene expression (Figure 2A). For each position in this middle zone, [A] and [R] make the left hand side of Equation (5) positive, and thus an enhancer with binding sites of affinity K which will switch from activation to repression at that position. Enhancers with TF binding sites of affinity greater than K have higher repressor occupancy and are repressed, while enhancers with binding sites of affinity lower than K are preferentially occupied by activators and drive gene expression (Figure 2A). Differences in TF binding site affinity thus produce distinct gene expression boundaries, but only within the middle zone of the gradient (Figure 2B). Outside of this middle region Equation (5) is not true, because [A] and [R] are such that the left half of Equation (5) is always negative, and all genes are either repressed (when [R]>[A]) or activated (when [A]2>[R]2ω) (Figure 2A). Therefore, outside the middle region of the OARG, differences in TF binding site affinity cannot produce different gene expression boundaries.


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)

Repressor cooperativity establishes a middle gradient zone in which distinct gene expression boundaries are possible. (A) Hh gradient and the corresponding Gli OARG. [A] and [R] range from 0 to 100 in arbitrary units, with fraction activator and repressor shown on the scale. Dashed lines indicate the boundaries of the middle gradient zone, as defined by Equations (6) and (7). (B) Under a cooperative model (ω=30), different enhancer affinities define distinct boundaries of gene activation. As enhancer affinity increases (as K increases), the region of gene activation is more restricted. (C) Under a non-cooperative model there is no middle zone in which multiple gene expression boundaries are possible, and all genes are activated when [A]>[R], regardless of affinity.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Repressor cooperativity establishes a middle gradient zone in which distinct gene expression boundaries are possible. (A) Hh gradient and the corresponding Gli OARG. [A] and [R] range from 0 to 100 in arbitrary units, with fraction activator and repressor shown on the scale. Dashed lines indicate the boundaries of the middle gradient zone, as defined by Equations (6) and (7). (B) Under a cooperative model (ω=30), different enhancer affinities define distinct boundaries of gene activation. As enhancer affinity increases (as K increases), the region of gene activation is more restricted. (C) Under a non-cooperative model there is no middle zone in which multiple gene expression boundaries are possible, and all genes are activated when [A]>[R], regardless of affinity.
Mentions: Equations (6) and (7) define the boundaries of a middle zone of the OARG in which differences in enhancer TF binding site affinity will produce different boundaries of gene expression (Figure 2A). For each position in this middle zone, [A] and [R] make the left hand side of Equation (5) positive, and thus an enhancer with binding sites of affinity K which will switch from activation to repression at that position. Enhancers with TF binding sites of affinity greater than K have higher repressor occupancy and are repressed, while enhancers with binding sites of affinity lower than K are preferentially occupied by activators and drive gene expression (Figure 2A). Differences in TF binding site affinity thus produce distinct gene expression boundaries, but only within the middle zone of the gradient (Figure 2B). Outside of this middle region Equation (5) is not true, because [A] and [R] are such that the left half of Equation (5) is always negative, and all genes are either repressed (when [R]>[A]) or activated (when [A]2>[R]2ω) (Figure 2A). Therefore, outside the middle region of the OARG, differences in TF binding site affinity cannot produce different gene expression boundaries.

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