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Transcriptional response to cardiac injury in the zebrafish: systematic identification of genes with highly concordant activity across in vivo models.

Rodius S, Nazarov PV, Nepomuceno-Chamorro IA, Jeanty C, González-Rosa JM, Ibberson M, da Costa RM, Xenarios I, Mercader N, Azuaje F - BMC Genomics (2014)

Bottom Line: Top candidates are significantly involved in cell fate specification and differentiation, and include heart failure markers such as periostin, as well as potential new targets for heart regeneration.Interestingly, a high activity of ptgis and ca2 has been previously observed in failing hearts from rats and humans.We identified genes with potential critical roles in the response to cardiac damage in the zebrafish.

View Article: PubMed Central - PubMed

Affiliation: NorLux Neuro-Oncology Laboratory, CRP-Santé, Luxembourg, Luxembourg. francisco.azuaje@crp-sante.lu.

ABSTRACT

Background: Zebrafish is a clinically-relevant model of heart regeneration. Unlike mammals, it has a remarkable heart repair capacity after injury, and promises novel translational applications. Amputation and cryoinjury models are key research tools for understanding injury response and regeneration in vivo. An understanding of the transcriptional responses following injury is needed to identify key players of heart tissue repair, as well as potential targets for boosting this property in humans.

Results: We investigated amputation and cryoinjury in vivo models of heart damage in the zebrafish through unbiased, integrative analyses of independent molecular datasets. To detect genes with potential biological roles, we derived computational prediction models with microarray data from heart amputation experiments. We focused on a top-ranked set of genes highly activated in the early post-injury stage, whose activity was further verified in independent microarray datasets. Next, we performed independent validations of expression responses with qPCR in a cryoinjury model. Across in vivo models, the top candidates showed highly concordant responses at 1 and 3 days post-injury, which highlights the predictive power of our analysis strategies and the possible biological relevance of these genes. Top candidates are significantly involved in cell fate specification and differentiation, and include heart failure markers such as periostin, as well as potential new targets for heart regeneration. For example, ptgis and ca2 were overexpressed, while usp2a, a regulator of the p53 pathway, was down-regulated in our in vivo models. Interestingly, a high activity of ptgis and ca2 has been previously observed in failing hearts from rats and humans.

Conclusions: We identified genes with potential critical roles in the response to cardiac damage in the zebrafish. Their transcriptional activities are reproducible in different in vivo models of cardiac injury.

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Related in: MedlinePlus

Predicted relationships betweenptgisand its candidate regulated genes are reproduced in the cryoinjury model at day-1 post-injury. Plots show the Log2FC observed in independent qPCR data validation at day-1 (in relation to sham-1d), which are qualitatively consistent with the associations predicted by the computational model inferred from public data (Figure 2B). Error bars: Standard errors based on expression variability of 3 biological replicates for experimental and control conditions.
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Fig6: Predicted relationships betweenptgisand its candidate regulated genes are reproduced in the cryoinjury model at day-1 post-injury. Plots show the Log2FC observed in independent qPCR data validation at day-1 (in relation to sham-1d), which are qualitatively consistent with the associations predicted by the computational model inferred from public data (Figure 2B). Error bars: Standard errors based on expression variability of 3 biological replicates for experimental and control conditions.

Mentions: Figures 6 and 7 illustrate the results from this independent test, and indicate a good reproducibility of predicted associations at day-1 and -3. This network model correctly described the qualitative gene-gene (fold-change) relationships observed in the validation dataset. The only exception to the latter was the response of sgce, which showed a Log2FC = 0.003, instead of the negative value predicted. An alternative visualization of the changes in (log2) expression of these genes is available in Additional file 4. This is further evidence of the predictive potential of this network model, and of the putative relevance of ptgis as a transcriptional control component in the early response to heart injury in both amputation and cryoinjury models.Figure 6


Transcriptional response to cardiac injury in the zebrafish: systematic identification of genes with highly concordant activity across in vivo models.

Rodius S, Nazarov PV, Nepomuceno-Chamorro IA, Jeanty C, González-Rosa JM, Ibberson M, da Costa RM, Xenarios I, Mercader N, Azuaje F - BMC Genomics (2014)

Predicted relationships betweenptgisand its candidate regulated genes are reproduced in the cryoinjury model at day-1 post-injury. Plots show the Log2FC observed in independent qPCR data validation at day-1 (in relation to sham-1d), which are qualitatively consistent with the associations predicted by the computational model inferred from public data (Figure 2B). Error bars: Standard errors based on expression variability of 3 biological replicates for experimental and control conditions.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4197235&req=5

Fig6: Predicted relationships betweenptgisand its candidate regulated genes are reproduced in the cryoinjury model at day-1 post-injury. Plots show the Log2FC observed in independent qPCR data validation at day-1 (in relation to sham-1d), which are qualitatively consistent with the associations predicted by the computational model inferred from public data (Figure 2B). Error bars: Standard errors based on expression variability of 3 biological replicates for experimental and control conditions.
Mentions: Figures 6 and 7 illustrate the results from this independent test, and indicate a good reproducibility of predicted associations at day-1 and -3. This network model correctly described the qualitative gene-gene (fold-change) relationships observed in the validation dataset. The only exception to the latter was the response of sgce, which showed a Log2FC = 0.003, instead of the negative value predicted. An alternative visualization of the changes in (log2) expression of these genes is available in Additional file 4. This is further evidence of the predictive potential of this network model, and of the putative relevance of ptgis as a transcriptional control component in the early response to heart injury in both amputation and cryoinjury models.Figure 6

Bottom Line: Top candidates are significantly involved in cell fate specification and differentiation, and include heart failure markers such as periostin, as well as potential new targets for heart regeneration.Interestingly, a high activity of ptgis and ca2 has been previously observed in failing hearts from rats and humans.We identified genes with potential critical roles in the response to cardiac damage in the zebrafish.

View Article: PubMed Central - PubMed

Affiliation: NorLux Neuro-Oncology Laboratory, CRP-Santé, Luxembourg, Luxembourg. francisco.azuaje@crp-sante.lu.

ABSTRACT

Background: Zebrafish is a clinically-relevant model of heart regeneration. Unlike mammals, it has a remarkable heart repair capacity after injury, and promises novel translational applications. Amputation and cryoinjury models are key research tools for understanding injury response and regeneration in vivo. An understanding of the transcriptional responses following injury is needed to identify key players of heart tissue repair, as well as potential targets for boosting this property in humans.

Results: We investigated amputation and cryoinjury in vivo models of heart damage in the zebrafish through unbiased, integrative analyses of independent molecular datasets. To detect genes with potential biological roles, we derived computational prediction models with microarray data from heart amputation experiments. We focused on a top-ranked set of genes highly activated in the early post-injury stage, whose activity was further verified in independent microarray datasets. Next, we performed independent validations of expression responses with qPCR in a cryoinjury model. Across in vivo models, the top candidates showed highly concordant responses at 1 and 3 days post-injury, which highlights the predictive power of our analysis strategies and the possible biological relevance of these genes. Top candidates are significantly involved in cell fate specification and differentiation, and include heart failure markers such as periostin, as well as potential new targets for heart regeneration. For example, ptgis and ca2 were overexpressed, while usp2a, a regulator of the p53 pathway, was down-regulated in our in vivo models. Interestingly, a high activity of ptgis and ca2 has been previously observed in failing hearts from rats and humans.

Conclusions: We identified genes with potential critical roles in the response to cardiac damage in the zebrafish. Their transcriptional activities are reproducible in different in vivo models of cardiac injury.

Show MeSH
Related in: MedlinePlus