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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

Candidate genes show significant concordance of expression patterns across independentin vivomodels at day-3 post-injury. Log2-transformed fold-changes (FC) observed at day-3 (in relation to controls). Independent observations show strong positive linear relationships (Pearson correlation coefficient: 0.84, coefficient of determination: 0.71).
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Fig5: Candidate genes show significant concordance of expression patterns across independentin vivomodels at day-3 post-injury. Log2-transformed fold-changes (FC) observed at day-3 (in relation to controls). Independent observations show strong positive linear relationships (Pearson correlation coefficient: 0.84, coefficient of determination: 0.71).

Mentions: We measured the expression of the candidate genes with qPCR 1 and 3 days after cryoinjury and from sham operated animals (3 injured vs. 3 sham samples for each time point). We assessed whether qPCR expression responses were consistent with those observed in the amputation model. We found a high concordance between the expression responses at day-1 from the model derivation and validation datasets (Figure 4). More specifically, strong positive linear correlations were detected between their (log2-transformed) expression fold-changes at day-1 (Pearson’s correlation, r = 0.77, P = 0.0008). Our validation experiments at day-3 also showed that the transcriptional response of our candidate genes is highly concordant between independent datasets and in vivo models. As before, we observed a high positive correlation between the derivation and validation datasets (r = 0.84, Figure 5).Figure 4


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)

Candidate genes show significant concordance of expression patterns across independentin vivomodels at day-3 post-injury. Log2-transformed fold-changes (FC) observed at day-3 (in relation to controls). Independent observations show strong positive linear relationships (Pearson correlation coefficient: 0.84, coefficient of determination: 0.71).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig5: Candidate genes show significant concordance of expression patterns across independentin vivomodels at day-3 post-injury. Log2-transformed fold-changes (FC) observed at day-3 (in relation to controls). Independent observations show strong positive linear relationships (Pearson correlation coefficient: 0.84, coefficient of determination: 0.71).
Mentions: We measured the expression of the candidate genes with qPCR 1 and 3 days after cryoinjury and from sham operated animals (3 injured vs. 3 sham samples for each time point). We assessed whether qPCR expression responses were consistent with those observed in the amputation model. We found a high concordance between the expression responses at day-1 from the model derivation and validation datasets (Figure 4). More specifically, strong positive linear correlations were detected between their (log2-transformed) expression fold-changes at day-1 (Pearson’s correlation, r = 0.77, P = 0.0008). Our validation experiments at day-3 also showed that the transcriptional response of our candidate genes is highly concordant between independent datasets and in vivo models. As before, we observed a high positive correlation between the derivation and validation datasets (r = 0.84, Figure 5).Figure 4

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