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Transcriptional double-autorepression feedforward circuits act for multicellularity and nervous system development.

Iwama H, Murao K, Imachi H, Ishida T - BMC Genomics (2011)

Bottom Line: In particular, an FFC comprising two repressors that are both autoregulated was revealed as a significant network motif, which we termed the double-autoregulation FFC (DAR-FFC).Interestingly, this network motif preferentially constitutes effecter transcriptional circuits with functions in cell-cell signaling and multicellular organization, and is particularly related to nervous system development.This is the first report showing that the DAR-FFC is a significant network motif.

View Article: PubMed Central - HTML - PubMed

Affiliation: Life Science Research Center, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan. iwama@med.kagawa-u.ac.jp

ABSTRACT

Background: The transcriptional regulatory network is considered to be built from a set of circuit patterns called network motifs. Experimental studies have provided instances where a feedforward circuit (FFC) appears with modification of autoregulation, but little is known systematically about such autoregulation-integrated FFCs. Therefore, we aimed to examine whether the autoregulation-integrated FFC is a network motif relevant to describing the human transcriptional regulatory systems, and explored the relationship of such network motifs with biological functions.

Results: Based on human-mouse evolutionarily conserved transcription factor binding sites (TFBSs) in 76600 conserved blocks for 5169 genes, we compiled the human transcriptional connections into a matrix, and examined the number of FFC appearances in comparison with randomized networks. The results revealed that the configuration of autoregulation integrated in the FFC critically affects the abundance or avoidance of FFC appearances. In particular, an FFC comprising two repressors that are both autoregulated was revealed as a significant network motif, which we termed the double-autoregulation FFC (DAR-FFC). Interestingly, this network motif preferentially constitutes effecter transcriptional circuits with functions in cell-cell signaling and multicellular organization, and is particularly related to nervous system development.

Conclusions: We have revealed that the configuration of autoregulation integrated in the FFCs is a critical factor for abundance or avoidance of the appearance of the FFCs. In particular, we have identified the DAR-FFC as a distinctive integrated network motif endowed with properties that are indispensable for forming the transcriptional regulatory circuits involved in multicellular organization and nervous system development. This is the first report showing that the DAR-FFC is a significant network motif.

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The changes in Z scores for the overrepresented motifs under assumption of perturbed regulator modes. The changes in the Z scores are shown in plots with closed triangles along the proportions with which the TF modes of the connections were randomly swapped between positive and negative. This perturbation procedure was repeated ten times with each proportion of 1%, 5%, 10%, 15% and 20% for (a) DAR-FFCs, (b) coherent FFCs and (c) coherent type-1 FFCs. The results show that the Z scores remain at statistically significant levels with mode perturbation of 1% through 20%. The closed circle on each y-axis represents the Z score of the main results (i.e. without perturbation).
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Figure 4: The changes in Z scores for the overrepresented motifs under assumption of perturbed regulator modes. The changes in the Z scores are shown in plots with closed triangles along the proportions with which the TF modes of the connections were randomly swapped between positive and negative. This perturbation procedure was repeated ten times with each proportion of 1%, 5%, 10%, 15% and 20% for (a) DAR-FFCs, (b) coherent FFCs and (c) coherent type-1 FFCs. The results show that the Z scores remain at statistically significant levels with mode perturbation of 1% through 20%. The closed circle on each y-axis represents the Z score of the main results (i.e. without perturbation).

Mentions: Since the mode (positive or negative) is not guaranteed for all of the predicted connections regulated by the positive and negative TFs, it is important to examine the robustness of the confidence of the results under the assumption that positive TFs partially act as negative TFs and vice versa. For this purpose, we performed mode perturbation analyses by swapping the modes of the connections regulated by positive and negative TFs with proportions of 1%, 5%, 10%, 15% and 20%. As a result, we confirmed that the Z scores that were statistically significant in the results remained at statistically significant levels after the positive-negative mode perturbations of 1% through 20% (Figures 4 and 5). The changes in the Z scores were seemingly paradoxical for the antimotifs (Figure 5), i.e. the effecter-targeting FFCs composed of an originating repressor regulator with autoregulation and an intermediary regulator without autoregulation irrespective of the mode, because these confidence levels increased despite the perturbation procedures. This phenomenon is considered to be consistent with the main results based on the following reasoning. Regardless of which originating and intermediary regulators are perturbed to positive or negative, these perturbed FFCs come to fall into the category of the originating-only autoregulated FFCs regardless of the mode (Figure 1b). Therefore, the mode perturbation procedures move the confidence levels for these FFCs closer to the confidence level of the category of the originating-only autoregulated FFCs targeting effecters, the Z score of which is -1.911 (Figure 1b). The plots in Figure 5 show that the Z scores for these antimotif FFCs move closer to the value of -1.911 with an increase in the proportion of the mode-perturbed connections. These observations demonstrate that the confidence of the main results is robust against perturbation of the mode assignments of the positive and negative TFs.


Transcriptional double-autorepression feedforward circuits act for multicellularity and nervous system development.

Iwama H, Murao K, Imachi H, Ishida T - BMC Genomics (2011)

The changes in Z scores for the overrepresented motifs under assumption of perturbed regulator modes. The changes in the Z scores are shown in plots with closed triangles along the proportions with which the TF modes of the connections were randomly swapped between positive and negative. This perturbation procedure was repeated ten times with each proportion of 1%, 5%, 10%, 15% and 20% for (a) DAR-FFCs, (b) coherent FFCs and (c) coherent type-1 FFCs. The results show that the Z scores remain at statistically significant levels with mode perturbation of 1% through 20%. The closed circle on each y-axis represents the Z score of the main results (i.e. without perturbation).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3116505&req=5

Figure 4: The changes in Z scores for the overrepresented motifs under assumption of perturbed regulator modes. The changes in the Z scores are shown in plots with closed triangles along the proportions with which the TF modes of the connections were randomly swapped between positive and negative. This perturbation procedure was repeated ten times with each proportion of 1%, 5%, 10%, 15% and 20% for (a) DAR-FFCs, (b) coherent FFCs and (c) coherent type-1 FFCs. The results show that the Z scores remain at statistically significant levels with mode perturbation of 1% through 20%. The closed circle on each y-axis represents the Z score of the main results (i.e. without perturbation).
Mentions: Since the mode (positive or negative) is not guaranteed for all of the predicted connections regulated by the positive and negative TFs, it is important to examine the robustness of the confidence of the results under the assumption that positive TFs partially act as negative TFs and vice versa. For this purpose, we performed mode perturbation analyses by swapping the modes of the connections regulated by positive and negative TFs with proportions of 1%, 5%, 10%, 15% and 20%. As a result, we confirmed that the Z scores that were statistically significant in the results remained at statistically significant levels after the positive-negative mode perturbations of 1% through 20% (Figures 4 and 5). The changes in the Z scores were seemingly paradoxical for the antimotifs (Figure 5), i.e. the effecter-targeting FFCs composed of an originating repressor regulator with autoregulation and an intermediary regulator without autoregulation irrespective of the mode, because these confidence levels increased despite the perturbation procedures. This phenomenon is considered to be consistent with the main results based on the following reasoning. Regardless of which originating and intermediary regulators are perturbed to positive or negative, these perturbed FFCs come to fall into the category of the originating-only autoregulated FFCs regardless of the mode (Figure 1b). Therefore, the mode perturbation procedures move the confidence levels for these FFCs closer to the confidence level of the category of the originating-only autoregulated FFCs targeting effecters, the Z score of which is -1.911 (Figure 1b). The plots in Figure 5 show that the Z scores for these antimotif FFCs move closer to the value of -1.911 with an increase in the proportion of the mode-perturbed connections. These observations demonstrate that the confidence of the main results is robust against perturbation of the mode assignments of the positive and negative TFs.

Bottom Line: In particular, an FFC comprising two repressors that are both autoregulated was revealed as a significant network motif, which we termed the double-autoregulation FFC (DAR-FFC).Interestingly, this network motif preferentially constitutes effecter transcriptional circuits with functions in cell-cell signaling and multicellular organization, and is particularly related to nervous system development.This is the first report showing that the DAR-FFC is a significant network motif.

View Article: PubMed Central - HTML - PubMed

Affiliation: Life Science Research Center, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan. iwama@med.kagawa-u.ac.jp

ABSTRACT

Background: The transcriptional regulatory network is considered to be built from a set of circuit patterns called network motifs. Experimental studies have provided instances where a feedforward circuit (FFC) appears with modification of autoregulation, but little is known systematically about such autoregulation-integrated FFCs. Therefore, we aimed to examine whether the autoregulation-integrated FFC is a network motif relevant to describing the human transcriptional regulatory systems, and explored the relationship of such network motifs with biological functions.

Results: Based on human-mouse evolutionarily conserved transcription factor binding sites (TFBSs) in 76600 conserved blocks for 5169 genes, we compiled the human transcriptional connections into a matrix, and examined the number of FFC appearances in comparison with randomized networks. The results revealed that the configuration of autoregulation integrated in the FFC critically affects the abundance or avoidance of FFC appearances. In particular, an FFC comprising two repressors that are both autoregulated was revealed as a significant network motif, which we termed the double-autoregulation FFC (DAR-FFC). Interestingly, this network motif preferentially constitutes effecter transcriptional circuits with functions in cell-cell signaling and multicellular organization, and is particularly related to nervous system development.

Conclusions: We have revealed that the configuration of autoregulation integrated in the FFCs is a critical factor for abundance or avoidance of the appearance of the FFCs. In particular, we have identified the DAR-FFC as a distinctive integrated network motif endowed with properties that are indispensable for forming the transcriptional regulatory circuits involved in multicellular organization and nervous system development. This is the first report showing that the DAR-FFC is a significant network motif.

Show MeSH